Viral polymerase inhibitors

ABSTRACT

An isomer, enantiomer, diastereoisomer, or tautomer of a compound, represented by formula I: 
                         
wherein:
     A is O, S, NR 1 , or CR 1 , wherein R 1  is defined herein;   — represents either a single or a double bond;   R 2  is selected from: H, halogen, R 21 , OR 21 , SR 21 , COOR 21 , SO 2 N(R 22 ) 2 , N(R 22 ) 2 , CON(R 22 ) 2 , NR 22 C(O)R 22  or NR 22 C(O)NR 22  wherein R 21  and each R 22  is defined herein;   B is NR 3  or CR 3 , with the proviso that one of A or B is either CR 1  or CR 3 , wherein R 3  is defined herein;   K is N or CR 4 , wherein R 4  is defined herein;   L is N or CR 5  wherein R 5  has the same definition as R 4  defined above;   M is N or CR 7 , wherein R 7  has the same definition as R 4  defined above;   Y 1  is O or S;   Z is N(R 6a )R 6  or OR 6 , wherein R 6a  is H or alkyl or NR 61 R 62  wherein R 61  and R 62  are defined herein;
 
a salt or a derivative thereof, as an inhibitor of HCV NS5B polymerase.

RELATED APPLICATIONS

This Application is a Divisional application of U.S. Ser. No.10/198,680, filed Jul. 18, 2002, for which benefit of U.S. Provisionalapplication Ser. No. 60/307,674 filed on Jul. 25, 2001, and U.S.Provisional application Ser. No. 60/338,061 filed on Dec. 7, 2001 ishereby claimed. These Provisional Applications are herein incorporatedby reference in their entirety.

TECHNICAL FIELD OF THE INVENTION

The invention relates to inhibitors of RNA dependent RNA polymerases,particularly those viral polymerases within the Flaviviridae family,more particularly to HCV polymerase.

BACKGROUND OF THE INVENTION

About 30,000 new cases of hepatitis C virus (HCV) infection areestimated to occur in the United States each year (Kolykhalov, A. A.;Mihalik, K.; Feinstone, S. M.; Rice, C. M.; 2000; J. Virol. 74:2046-2051*). HCV is not easily cleared by the hosts' immunologicaldefences; as many as 85% of the people infected with HCV becomechronically infected. Many of these persistent infections result inchronic liver disease, including cirrhosis and hepatocellular carcinoma(Hoofnagle, J. H.; 1997; Hepatology 26: 15S-20S*). There are anestimated 170 million HCV carriers world-wide, and HCV-associatedend-stage liver disease is now the leading cause of livertransplantation. In the United States alone, hepatitis C is responsiblefor 8,000 to 10,000 deaths annually. Without effective intervention, thenumber is expected to triple in the next 10 to 20 years. There is novaccine to prevent HCV infection. Prolonged treatment of chronicallyinfected patients with interferon or interferon and ribavirin is theonly currently approved therapy, but it achieves a sustained response infewer than 50% of cases (Lindsay, K. L.; 1997; Hepatology 26: 71S-77S*,and Reichard, O.; Schvarcz, R.; Weiland, O.; 1997 Hepatology 26:108S-111S*). * incorporated herein by reference

HCV belongs to the family Flaviviridae, genus hepacivirus, whichcomprises three genera of small enveloped positive-strand RNA viruses(Rice, C. M.; 1996; “Flaviviridae: the viruses and their replication”;pp. 931-960 in Fields Virology; Fields, B. N.; Knipe, D. M.; Howley, P.M. (eds.); Lippincott-Raven Publishers, Philadelphia Pa.*). The 9.6 kbgenome of HCV consists of a long open reading frame (ORF) flanked by 5′and 3′ non-translated regions (NTR's). The HCV 5′ NTR is 341 nucleotidesin length and functions as an internal ribosome entry site forcap-independent translation initiation (Lemon, S. H.; Honda, M.; 1997;Semin. Virol. 8: 274-288*). The HCV polyprotein is cleaved co- andpost-translationally into at least 10 individual polypeptides (Reed, K.E.; Rice, C. M.; 1999; Curr. Top. Microbiol. Immunol. 242: 55-84*). Thestructural proteins result from signal peptidases in the N-terminalportion of the polyprotein. Two viral proteases mediate downstreamcleavages to produce non-structural (NS) proteins that function ascomponents of the HCV RNA replicase. The NS2-3 protease spans theC-terminal half of the NS2 and the N-terminal one-third of NS3 andcatalyses cis cleavage of the NS2/3 site. The same portion of NS3 alsoencodes the catalytic domain of the NS3-4A serine protease that cleavesat four downstream sites. The C-terminal two-thirds of NS3 is highlyconserved amongst HCV isolates, with RNA-binding, RNA-stimulated NTPase,and RNA unwinding activities. Although NS4B and the NS5A phosphoproteinare also likely components of the replicase, their specific roles areunknown. The C-terminal polyprotein cleavage product, NS5B, is theelongation subunit of the HCV replicase possessing RNA-dependent RNApolymerase (RdRp) activity (Behrens, S. E.; Tomei, L.; DeFrancesco, R.;1996; EMBO J. 15: 12-22*; and Lohmann, V.; Kömer, F.; Herian, U.;Bartenschlager, R.; 1997; J. Virol. 71: 8416-8428*). It has beenrecently demonstrated that mutations destroying NS5B activity abolishinfectivity of RNA in a chimp model (Kolykhalov, A. A.; Mihalik, K.;Feinstone, S. M.; Rice, C. M.; 2000; J. Virol. 74: 2046-2051*). *incorporated herein by reference

The development of new and specific anti-HCV treatments is a highpriority, and virus-specific functions essential for replication are themost attractive targets for drug development. The absence of RNAdependent RNA polymerases in mammals, and the fact that this enzymeappears to be essential to viral replication, would suggest that theNS5B polymerase is an ideal target for anti-HCV therapeutics.

WO 00/06529 reports inhibitors of NS5B which are α, γ-diketoacids.

WO 00/13708, WO 00/10573, WO 00/18231, and WO 01/47883 report inhibitorsof NS5B proposed for treatment of HCV.

SUMMARY OF THE INVENTION

It is therefore an object of the invention to provide a novel series ofcompounds having improved inhibitory activity against HCV polymerase.

In a first aspect of the invention, there is provided an isomer,enantiomer, diastereoisomer, or tautomer of a compound, represented byformula I:

wherein:A is O, S, NR¹, or CR¹, wherein R¹ is selected from the group consistingof: H, (C₁₋₆)alkyl optionally substituted with:

-   -   halogen, OR¹¹, SR¹¹ or N(R¹²)₂, wherein R¹¹ and each R¹² is        independently H, (C₁₋₆)alkyl, (C₃₋₇)cycloalkyl,        (C₁₋₆)alkyl-(C₃₋₇)cycloalkyl, (C₁₋₆)alkyl-aryl or        (C₁₋₆)alkyl-Het, said aryl or Het optionally substituted with        R¹⁰; or    -   both R¹² are covalently bonded together and to the nitrogen to        which they are both attached to form a 5, 6 or 7-membered        saturated heterocycle;        — represents either a single or a double bond;        R² is selected from: H, halogen, R²¹, OR²¹, SR²¹, COOR²¹,        SO₂N(R²²)₂, N(R²²)₂, CON(R²²)₂, NR²²C(O)R²² or NR²²C(O)NR²²        wherein R²¹ and each R²² is independently H, (C₁₋₆)alkyl,        haloalkyl, (C₂₋₆)alkenyl, (C₃₋₇)cycloalkyl, (C₂₋₆)alkynyl,        (C₅₋₇)cycloalkenyl, 6 or 10-membered aryl or Het, said R²¹ and        R²² being optionally substituted with R²⁰, or both R²² are        bonded together to form a 5, 6 or 7-membered saturated        heterocycle with the nitrogen to which they are attached;        wherein R¹⁰ and R²⁰ is each:    -   1 to 4 substituents selected from: halogen, OPO₃H, NO₂, cyano,        azido, C(═NH)NH₂, C(═NH)NH(C₁₋₆)alkyl or C(═NH)NHCO(C₁₋₆)alkyl;        or    -   1 to 4 substituents selected from:    -   a) (C₁₋₆) alkyl or haloalkyl, (C₃₋₇)cycloalkyl, C₃₋₇        spirocycloalkyl optionally containing 1 or 2 heteroatom,        (C₂₋₆)alkenyl, (C₃₋₆)cycloalkenyl, (C₂₋₈)alkynyl, (C₁₋₆)        alkyl-(C₃₋₇)cycloalkyl, all of which optionally substituted with        R¹⁵⁰;    -   b) OR¹⁰⁴ wherein R¹⁰⁴ is H, (C₁₋₆alkyl), (C₃₋₇)cycloalkyl, or        (C₁₋₆)alkyl-(C₃₋₇)cycloalkyl, aryl, Het, (C₁₋₆alkyl)aryl or        (C₁₋₆alkyl)Het, said alkyl, cycloalkyl, aryl, Het,        (C₁₋₆alkyl)aryl or (C₁₋₆alkyl)Het being optionally substituted        with R¹⁵⁰;    -   c) OCOR¹⁰⁵ wherein R¹⁰⁵ is (C₁₋₆)alkyl, (C₃₋₇)cycloalkyl,        (C₁₋₆)alkyl-(C₃₋₇)cycloalkyl, Het, (C₁₋₆alkyl)aryl or        (C₁₋₆alkyl)Het, said alkyl, cycloalkyl, aryl, Het,        (C₁₋₆alkyl)aryl or (C₁₋₆alkyl)Het being optionally substituted        with R¹⁵⁰;    -   d) SR¹⁰⁸, SO₂N(R¹⁰⁸)₂ or SO₂N(R¹⁰⁸)C(O)R¹⁰⁸ wherein each R¹⁰⁸ is        independently H, (C₁₋₆)alkyl, (C₃₋₇)cycloalkyl or        (C₁₋₆)alkyl-(C₃₋₇)cycloalkyl, aryl, Het, (C₁₋₆alkyl)aryl or        (C₁₋₆alkyl)Het or both R¹⁰⁸ are covalently bonded together and        to the nitrogen to which they are attached to form a 5, 6 or        7-membered saturated heterocycle, said alkyl, cycloalkyl, aryl,        Het, (C₁₋₆alkyl)aryl or (C₁₋₆alkyl)Het or heterocycle being        optionally substituted with R¹⁵⁰;    -   e) NR¹¹¹R¹¹² wherein R¹¹¹ is H, (C₁₋₆)alkyl, (C₃₋₇)cycloalkyl or        (C₁₋₆)alkyl-(C₃₋₇)cycloalkyl, aryl, Het, (C₁₋₆alkyl)aryl or        (C₁₋₆alkyl)Het, and R¹¹² is H, CN, (C₁₋₆)alkyl, (C₃₋₇)cycloalkyl        or (C₁₋₆)alkyl-(C₃₋₇)cycloalkyl, aryl, Het, (C₁₋₆alkyl)aryl,        (C₁₋₆alkyl)Het, COOR¹¹⁵ or SO₂R¹¹⁵ wherein R¹¹⁵ is (C₁₋₆)alkyl,        (C₃₋₇)cycloalkyl, or (C₁₋₆)alkyl-(C₃₋₇)cycloalkyl, aryl, Het,        (C₁₋₆alkyl)aryl or (C₁₋₆alkyl)Het, or both R¹¹¹ and R¹¹² are        covalently bonded together and to the nitrogen to which they are        attached to form a 5, 6 or 7-membered saturated heterocycle,        said alkyl, cycloalkyl, aryl, Het, (C₁₋₆alkyl)aryl or        (C₁₋₆alkyl)Het, or heterocycle being optionally substituted with        R¹⁵⁰;    -   f) NR¹¹⁶COR¹¹⁷ wherein R¹¹⁶ and R¹¹⁷ is each H, (C₁₋₆)alkyl,        (C₃₋₇)cycloalkyl, (C₁₋₆)alkyl-(C₃₋₇)cycloalkyl, aryl, Het,        (C₁₋₆alkyl)aryl or (C₁₋₆alkyl)Het, said (C₁₋₆)alkyl,        (C₃₋₇)cycloalkyl, (C₁₋₆)alkyl-(C₃₋₇)cycloalkyl, aryl, Het,        (C₁₋₆alkyl)aryl or (C₁₋₆alkyl)Het being optionally substituted        with R¹⁵⁰;    -   g) NR¹¹⁸CONR¹¹⁹R¹²⁰, wherein R¹¹⁸, R¹¹⁹ and R¹²⁰ is each H,        (C₁₋₆)alkyl, (C₃₋₇)cycloalkyl, (C₁₋₆)alkyl-(C₃₋₇)cycloalkyl,        aryl, Het, (C₁₋₆alkyl)aryl or (C₁₋₆alkyl)Het, or R¹¹⁸ is        covalently bonded to R¹¹⁹ and to the nitrogen to which they are        attached to form a 5, 6 or 7-membered saturated heterocycle;    -   or R¹¹⁹ and R¹²⁰ are covalently bonded together and to the        nitrogen to which they are attached to form a 5, 6 or 7-membered        saturated heterocycle;    -   said alkyl, cycloalkyl, (C₁₋₆)alkyl-(C₃₋₇)cycloalkyl, aryl, Het,        (C₁₋₆alkyl)aryl or (C₁₋₆alkyl)Het or heterocycle being        optionally substituted with R¹⁵⁰;    -   h) NR¹²¹COCOR¹²² wherein R¹²¹ and R¹²² is each H, (C₁₋₆)alkyl,        (C₃₋₇)cycloalkyl, (C₁₋₆)alkyl-(C₃₋₇)cycloalkyl, a 6- or        10-membered aryl, Het, (C₁₋₆alkyl)aryl or (C₁₋₆alkyl)Het, said        alkyl, cycloalkyl, alkyl-cycloalkyl, aryl, Het, (C₁₋₆alkyl)aryl        or (C₁₋₆alkyl)Het being optionally substituted with R¹⁵⁰; or        R¹²² is OR¹²³ or N(R¹²⁴)₂ wherein R¹²³ and each R¹²⁴ is        independently H (C₁₋₆alkyl), (C₃₋₇)cycloalkyl, or        (C₁₋₆)alkyl-(C₃₋₇)cycloalkyl, aryl, Het, (C₁₋₆alkyl)aryl or        (C₁₋₆alkyl)Het, or R¹²⁴ is OH or O(C₁₋₆alkyl) or both R¹²⁴ are        covalently bonded together to form a 5, 6 or 7-membered        saturated heterocycle, said alkyl, cycloalkyl, alkyl-cycloalkyl,        aryl, Het, (C₁₋₆alkyl)aryl or (C₁₋₆alkyl)Het and heterocycle        being optionally substituted with R¹⁵⁰;    -   i) COR¹²⁷ wherein R¹²⁷ is H, (C₁₋₆)alkyl, (C₃₋₇)cycloalkyl or        (C₁₋₆)alkyl-(C₃₋₇)cycloalkyl, aryl, Het, (C₁₋₆alkyl)aryl or        (C₁₋₆alkyl)Het, said alkyl, cycloalkyl, aryl, Het,        (C₁₋₆alkyl)aryl or (C₁₋₆alkyl)Het being optionally substituted        with R¹⁵⁰;    -   j) COOR¹²⁸ wherein R¹²⁸ is H, (C₁₋₆)alkyl, (C₃₋₇)cycloalkyl, or        (C₁₋₆)alkyl-(C₃₋₇)cycloalkyl, aryl, Het, (C₁₋₆alkyl)aryl or        (C₁₋₆alkyl)Het, said (C₁₋₆)alkyl, (C₃₋₇)cycloalkyl, or        (C₁₋₆)alkyl-(C₃₋₇)cycloalkyl, aryl, Het, (C₁₋₆alkyl)aryl and        (C₁₋₆alkyl)Het being optionally substituted with R¹⁵⁰;    -   k) CONR¹²⁹R¹³⁰ wherein R¹²⁹ and R¹³⁰ are independently H,        (C₁₋₆)alkyl (C₃₋₇)cycloalkyl, (C₁₋₆)alkyl-(C₃₋₇)cycloalkyl,        aryl, Het, (C₁₋₆alkyl)aryl or (C₁₋₆alkyl)Het, or both R¹²⁹ and        R¹³⁰ are covalently bonded together and to the nitrogen to which        they are attached to form a 5, 6 or 7-membered saturated        heterocycle, said alkyl, cycloalkyl, alkyl-cycloalkyl, aryl,        Het, (C₁₋₆alkyl)aryl, (C₁₋₆alkyl)Het and heterocycle being        optionally substituted with R¹⁵⁰;    -   l) aryl, Het, (C₁₋₆alkyl)aryl or (C₁₋₆alkyl)Het, all of which        being optionally substituted with R¹⁵⁰; and        -   wherein R¹⁵⁰ is defined as:        -   1 to 3 substituents selected from: halogen, OPO₃H, NO₂,            cyano, azido, C(═NH)NH₂, C(═NH)NH(C₁₋₆)alkyl or            C(═NH)NHCO(C₁₋₆)alkyl; or        -   1 to 3 substituents selected from:        -   a) (C₁₋₆) alkyl or haloalkyl, (C₃₋₇)cycloalkyl, C₃₋₇            spirocycloalkyl optionally containing 1 or 2 heteroatom,            (C₂₋₆)alkenyl, (C₂₋₈)alkynyl, (C₁₋₆) alkyl-(C₃₋₇)cycloalkyl,            all of which optionally substituted with R¹⁶⁰;        -   b) OR¹⁰⁴ wherein R¹⁰⁴ is H, (C₁₋₆alkyl), (C₃₋₇)cycloalkyl,            or (C₁₋₆)alkyl-(C₃₋₇)cycloalkyl, aryl, Het, (C₁₋₆alkyl)aryl            or (C₁₋₆alkyl)Het, said alkyl, cycloalkyl, aryl, Het,            (C₁₋₆alkyl)aryl or (C₁₋₆alkyl)Het being optionally            substituted with R¹⁶⁰;        -   c) OCOR¹⁰⁵ wherein R¹⁰⁵ is (C₁₋₆)alkyl, (C₃₋₇)cycloalkyl,            (C₁₋₆)alkyl-(C₃₋₇)cycloalkyl, Het, (C₁₋₆alkyl)aryl or            (C₁₋₆alkyl)Het, said alkyl, cycloalkyl, aryl, Het,            (C₁₋₆alkyl)aryl or (C₁₋₆alkyl)Het being optionally            substituted with R¹⁶⁰;        -   d) SR¹⁰⁸, SO₂N(R¹⁰⁸)₂ or SO₂N(R¹⁰⁸)C(O)R¹⁰⁸ wherein each            R¹⁰⁸ is independently H, (C₁₋₆)alkyl, (C₃₋₇)cycloalkyl or            (C₁₋₆)alkyl-(C₃₋₇)cycloalkyl, aryl, Het, (C₁₋₆alkyl)aryl or            (C₁₋₆alkyl)Het or both R¹⁰⁸ are covalently bonded together            and to the nitrogen to which they are attached to form a 5,            6 or 7-membered saturated heterocycle, said alkyl,            cycloalkyl, aryl, Het, (C₁₋₆alkyl)aryl or (C₁₋₆alkyl)Het or            heterocycle being optionally substituted with R¹⁶⁰;        -   e) NR¹¹¹R¹¹² wherein R¹¹¹ is H, (C₁₋₆)alkyl,            (C₃₋₇)cycloalkyl or (C₁₋₆)alkyl-(C₃₋₇)cycloalkyl, aryl, Het,            (C₁₋₆alkyl)aryl or (C₁₋₆alkyl)Het, and R¹¹² is H, CN,            (C₁₋₆)alkyl, (C₃₋₇)cycloalkyl or            (C₁₋₆)alkyl-(C₃₋₇)cycloalkyl, aryl, Het, (C₁₋₆alkyl)aryl,            (C₁₋₆alkyl)Het, COOR¹¹⁵ or SO₂R¹¹⁵ wherein R¹¹⁵ is            (C₁₋₆)alkyl, (C₃₋₇)cycloalkyl, or            (C₁₋₆)alkyl-(C₃₋₇)cycloalkyl, aryl, Het, (C₁₋₆alkyl)aryl or            (C₁₋₆alkyl)Het, or both R¹¹¹ and R¹¹² are covalently bonded            together and to the nitrogen to which they are attached to            form a 5, 6 or 7-membered saturated heterocycle, said alkyl,            cycloalkyl, aryl, Het, (C₁₋₆alkyl)aryl or (C₁₋₆alkyl)Het, or            heterocycle being optionally substituted with R¹⁶⁰;        -   f) NR¹¹⁶COR¹¹⁷ wherein R¹¹⁶ and R¹¹⁷ is each H, (C₁₋₆)alkyl,            (C₃₋₇)cycloalkyl, (C₁₋₆)alkyl-(C₃₋₇)cycloalkyl, aryl, Het,            (C₁₋₆alkyl)aryl or (C₁₋₆alkyl)Het, said (C₁₋₆)alkyl,            (C₃₋₇)cycloalkyl, (C₁₋₆)alkyl-(C₃₋₇)cycloalkyl, aryl, Het,            (C₁₋₆alkyl)aryl or (C₁₋₆alkyl)Het being optionally            substituted with R¹⁶⁰;        -   g) NR¹¹⁸CONR¹¹⁹R¹²⁰ wherein R¹¹⁸, R¹¹⁹ and R¹²⁰ is each H,            (C₁₋₆)alkyl, (C₃₋₇)cycloalkyl, (C₁₋₆)alkyl-(C₃₋₇)cycloalkyl,            aryl, Het, (C₁₋₆alkyl)aryl or (C₁₋₆alkyl)Het, or R¹¹⁸ is            covalently bonded to R¹¹⁹ and to the nitrogen to which they            are attached to form a 5, 6 or 7-membered saturated            heterocycle;        -   or R¹¹⁹ and R¹²⁰ are covalently bonded together and to the            nitrogen to which they are attached to form a 5, 6 or            7-membered saturated heterocycle;        -   said alkyl, cycloalkyl, (C₁₋₆)alkyl-(C₃₋₇)cycloalkyl, aryl,            Het, (C₁₋₆alkyl)aryl or (C₁₋₆alkyl)Het or heterocycle being            optionally substituted with R¹⁶⁰;        -   h) NR¹²¹COCOR¹²² wherein R¹²¹ and R¹²² is each H,            (C₁₋₆)alkyl, (C₃₋₇)cycloalkyl, (C₁₋₆)alkyl-(C₃₋₇)cycloalkyl,            a 6- or 10-membered aryl, Het, (C₁₋₆alkyl)aryl or            (C₁₋₆alkyl)Het, said alkyl, cycloalkyl, alkyl-cycloalkyl,            aryl, Het, (C₁₋₆alkyl)aryl or (C₁₋₆alkyl)Het being            optionally substituted with R¹⁶⁰;        -   or R¹²² is OR¹²³ or N(R¹²⁴)₂ wherein R¹²³ and each R¹²⁴ is            independently H, (C₁₋₆alkyl), (C₃₋₇)cycloalkyl, or            (C₁₋₆)alkyl-(C₃₋₇)cycloalkyl, aryl, Het, (C₁₋₆alkyl)aryl or            (C₁₋₆alkyl)Het, or R¹²⁴ is OH or O(C₁₋₆alkyl) or both R¹²⁴            are covalently bonded together to form a 5, 6 or 7-membered            saturated heterocycle, said alkyl, cycloalkyl,            alkyl-cycloalkyl, aryl, Het, (C₁₋₆alkyl)aryl or            (C₁₋₆alkyl)Het and heterocycle being optionally substituted            with R¹⁶⁰;        -   i) COR¹²⁷ wherein R¹²⁷ is H, (C₁₋₆)alkyl, (C₃₋₇)cycloalkyl            or (C₁₋₆)alkyl-(C₃₋₇)cycloalkyl, aryl, Het, (C₁₋₆alkyl)aryl            or (C₁₋₆alkyl)Het, said alkyl, cycloalkyl, aryl, Het,            (C₁₋₆alkyl)aryl or (C₁₋₆alkyl)Het being optionally            substituted with R¹⁶⁰;        -   j) tetrazole, COOR¹²⁸ wherein R¹²⁸ is H, (C₁₋₆)alkyl,            (C₃₋₇)cycloalkyl, or (C₁₋₆)alkyl-(C₃₋₇)cycloalkyl, aryl,            Het, (C₁₋₆alkyl)aryl or (C₁₋₆alkyl)Het, said (C₁₋₆)alkyl,            (C₃₋₇)cycloalkyl, or (C₁₋₆)alkyl-(C₃₋₇)cycloalkyl, aryl,            Het, (C₁₋₆alkyl)aryl and (C₁₋₆alkyl)Het being optionally            substituted with R¹⁶⁰; and        -   k) CONR¹²⁹R¹³⁰ wherein R¹²⁹ and R¹³⁰ are independently H,            (C₁₋₆)alkyl, (C₃₋₇)cycloalkyl, (C₁₋₆)alkyl-(C₃₋₇)cycloalkyl,            aryl, Het, (C₁₋₆alkyl)aryl or (C₁₋₆alkyl)Het, or both R¹²⁹            and R¹³⁰ are covalently bonded together and to the nitrogen            to which they are attached to form a 5, 6 or 7-membered            saturated heterocycle, said alkyl, cycloalkyl,            alkyl-cycloalkyl, aryl, Het, (C₁₋₆alkyl)aryl, (C₁₋₆alkyl)Het            and heterocycle being optionally substituted with R¹⁶⁰;            -   wherein R¹⁶⁰ is defined as 1 or 2 substituents selected                from: tetrazole, halogen, CN, C₁₋₆alkyl, haloalkyl,                COOR¹⁶¹, SO₃H, SR¹⁶¹, SO₂R¹⁶¹, OR¹⁶¹, N(R¹⁶²)₂,                SO₂N(R¹⁶²)₂, NR¹⁶²COR¹⁶² or CON(R¹⁶²)₂ wherein R¹⁶¹ and                each R¹⁶² is independently H, (C₁₋₆)alkyl,                (C₃₋₇)cycloalkyl or (C₁₋₆)alkyl-(C₃₋₇)cycloalkyl; or                both R¹⁶² are covalently bonded together and to the                nitrogen to which they are attached to form a 5, 6 or                7-membered saturated heterocycle,                B is NR³ or CR³ with the proviso that one of A or B is                either CR¹ or CR³, wherein R³ is selected from                (C₁₋₆)alkyl, haloalkyl, (C₃₋₇)cycloalkyl,                (C₅₋₇)cycloalkenyl, (C₆₋₁₀)bicycloalkyl,                (C₆₋₁₀)bicycloalkenyl, 6- or 10-membered aryl, Het,                (C₁₋₆)alkyl-aryl or (C₁₋₆)alkyl-Het,    -   said alkyl, cycloalkyl, bicycloalkyl, aryl, Het, alkyl-aryl and        alkyl-Het being optionally substituted with from 1 to 4        substituents selected from: halogen, or        -   a) (C₁₋₆)alkyl optionally substituted with:            -   OR³¹ or SR³¹ wherein R³¹ is H, (C₁₋₆alkyl),                (C₃₋₇)cycloalkyl, (C₁₋₆)alkyl-(C₃₋₇)cycloalkyl, aryl,                Het, (C₁₋₆)alkyl-aryl or (C₁₋₆)alkyl-Het; or            -   N(R³²)₂ wherein each R³² is independently H,                (C₁₋₆)alkyl, (C₃₋₇)cycloalkyl,                (C₁₋₆)alkyl-(C₃₋₇)cycloalkyl, aryl, Het,                (C₁₋₆)alkyl-aryl or (C₁₋₆)alkyl-Het; or both R³² are                covalently bonded together and to the nitrogen to which                they are attached to form a 5, 6 or 7-membered saturated                heterocycle;        -   b) OR³³ wherein R³³ is H, (C₁₋₆)alkyl, (C₃₋₇)cycloalkyl or            (C₁₋₆)alkyl-(C₃₋₇)cycloalkyl, aryl, Het, (C₁₋₆)alkyl-aryl or            (C₁₋₆)alkyl-Het;        -   c) SR³⁴ wherein R³⁴ is H, (C₁₋₆)alkyl, (C₃₋₇)cycloalkyl, or            (C₁₋₆)alkyl-(C₃₋₇)cycloalkyl, aryl, Het, (C₁₋₆)alkyl-aryl or            (C₁₋₆)alkyl-Het; and        -   d) N(R³⁵)₂ wherein each R³⁵ is independently H, (C₁₋₆)alkyl,            (C₃₋₇)cycloalkyl, (C₁₋₆)alkyl-(C₃₋₇)cycloalkyl, aryl, Het,            (C₁₋₆)alkyl-aryl or (C₁₋₆)alkyl-Het; or both R³⁵ are            covalently bonded together and to the nitrogen to which they            are attached to form a 5, 6 or 7-membered saturated            heterocycle;            K is N or CR⁴, wherein R⁴ is H, halogen, (C₁₋₆)alkyl,            haloalkyl, (C₃₋₇)cycloalkyl or (C₁₋₆)alkyl-(C₃₋₇)cycloalkyl;            or R⁴ is OR⁴¹ or SR⁴¹, COR⁴¹ or NR⁴¹COR⁴¹ wherein each R⁴¹            is independently H, (C₁₋₆)alkyl), (C₃₋₇)cycloalkyl or            (C₁₋₆)alkyl-(C₃₋₇)cycloalkyl;            or R⁴ is NR⁴²R⁴³ wherein R⁴² and R⁴³ are each independently            H, (C₁₋₆)alkyl, (C₃₋₇)cycloalkyl,            (C₁₋₆)alkyl-(C₃₋₇)cycloalkyl, or both R⁴² and R⁴³ are            covalently bonded together and to the nitrogen to which they            are attached to form a 5, 6 or 7-membered saturated            heterocycle;            L is N or CR⁵, wherein R⁵ has the same definition as R⁴            defined above;            M is N or CR⁷, wherein R⁷ has the same definition as R⁴            defined above;            Y¹ is O or S;            Z is OR⁶, wherein R⁶ is H, (C₁₋₆)alkyl being optionally            substituted with: halo, hydroxy, carboxy, amino, C₁₋₆            alkoxy, C₁₋₆alkoxycarbonyl, and C₁₋₆ alkylamino; or R⁶ is            C₁₋₆ alkylaryl optionally substituted with: halogen, cyano,            nitro, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₁₋₆alkanoyl,            —(CH₂)₁₋₆—COOR⁷, —(CH₂)₁₋₆—CONR⁷R⁸, —(CH₂)₁₋₆—NR⁷R⁸,            —(CH₂)₁₋₆—NR⁷COR⁸, —(CH₂)₁₋₆—NHSO₂R⁷, —(CH₂)₁₋₆—OR⁷,            —(CH₂)₁₋₆—SR⁷, —(CH₂)₁₋₆—SO₂R⁷, and —(CH₂)₁₋₆—SO₂NR⁷R⁸,            wherein each R⁷ and each R⁸ is H or C₁₋₆ alkyl,            or Z is NR⁹R¹⁰ wherein each of R⁹ and R¹⁰ is selected from:            H, C₁₋₆alkoxy, or C₁₋₆alkyl optionally substituted with            halo, hydroxy, carboxy, amino, C₁₋₆ alkoxy,            C₁₋₆alkoxycarbonyl, and C₁₋₆ alkylamino;            or a salt thereof;            with the proviso that when A is CR¹, R¹ is Me, R² is            pyridine or

B is NR³, R³ is Me, K, L, M is CH, Y¹ is O, and Z is OR⁶, then R⁶ is notH;and with the proviso that when A is NR¹, R¹ is H, R² is phenyl, B isCR³, R³ is phenyl, K, L, M is CH, Y¹ is O, and Z is OR⁶, then R⁶ is notH;and with the proviso that when A is S, R² is bromine, B is CR³, R³ isMe, K is CH, L is CH, M is CR⁷, R⁷ is H or Me, Y¹ is O, and Z is OR⁶,then R⁶ is not H;and with the proviso that when A is O, R² is H, B is CR³, R³ is phenyl,K, L, M is CH, Y¹ is O and Z is OR⁶, then R⁶ is not H;and with the proviso that when A is CR¹, R¹ is Me, R² is pyridine, B isNR³, R³ is Me, K, L, M is CH, Y¹ is O, and Z is OR⁶, then R⁶ is not Me;and with the further proviso that when A is CR¹, R¹ is Me, R² is

B is NR³, R³ is Me, K, L, M is CH, Y¹ is O and Z is OR⁶, then R⁶ is notEt; and with the further proviso that when A is CR¹, R¹ is CH, R² is Me,B is NR³, R³ is Me, K, L, M is CH, Y¹ is O and Z is OR⁶, then R⁶ is notEt;and with the further proviso that when A is CR¹, R¹ is Et, R² is Me, Bis NR³, R³ is Me, K, L, M is CH, Y¹ is O, and Z is OR⁶, then R⁶ is notCH₂CH₂N(Me)₂;and with the further proviso that when A is CH, R² is Me, B is NR³, R³is

K is N, L is CR⁵, R⁵ is Me, M is CR⁷, R⁷ is OH, Y¹ is O, and Z is OR⁶then R⁶ is not Et;and with the further proviso that when A is NR¹, R¹ is Me, R² is Br, Bis CR³, R³ is

K is N, L is CR⁵, R⁵ is Me, M is CR⁷, R⁷ is Br, Y¹ is O, and Z is OR⁶,then R⁶ is not Me;and with the further proviso that when A is NR¹, R¹ is H, R² is Cl, B isCR³, R³ is Et, K is CH, L is CH, M is CH, Y¹ is O, Z is OR⁶, then R⁶ isnot Me;and with the further proviso that when A is NR¹, R¹ is H, R² is phenyl,B is CR³, R³ is phenyl, K is CH, L is CH, M is CR⁷, R⁷ is Me, Y¹ is O, Zis OR⁶, then R⁶ is not Et;and with the further proviso that when A is NR¹, R¹ is H, R² is

B is CR³, R³ is

K is CH. L is N, M is CH, Y¹ is O, and Z is OR⁶, then R⁶ is not Et;with the further proviso that when A is S, R² is Br, B is CR³, R³ is Me,K is CH, L is CH, M is CH, Y¹ is O, and Z is OR⁶, then R⁶ is not Me;and with the further proviso that, when A is NR¹, R¹ is H, R² is:

B is NR³, R³ is cyclohexyl, K, L, M is CH, Y¹ is O, Z is OR⁶, then R⁶ isnot H.

Alternatively, in a first aspect of the invention, there is provided acompound represented by Formula Ia:

wherein:A is O, S, NR¹, or CR¹;B is NR³ or CR³;R¹ is selected from the group consisting of: H(C₁₋₆)alkyl, benzyl, (C₁₋₆alkyl)-(C₆₋₁₀aryl), (C₁₋₆ alkyl)-5- or 6-membered heterocycle having 1to 4 heteroatoms selected from O, N, and S, and 5- or 6-memberedheterocycle having 1 to 4 heteroatoms selected from O, N and S,

-   -   wherein said benzyl and said heteroatom are optionally        substituted with from 1 to 4 substituents selected from the        group consisting of: COOH, COO(C₁₋₆ alkyl), halogen, and (C₁₋₆        alkyl);        R² is selected from the group consisting of: H, halogen,        (C₁₋₆)alkyl, (C₃₋₇)cycloalkyl, phenyl, 5- or 6-membered        heterocycle having 1 to 4 heteroatoms selected from O, N, and S,        pyridine-N-oxide, and 9- or 10-membered heterobicycle having 1        to 4 heteroatoms selected from O, N and S,    -   said phenyl, heterocycle and heterobicycle being optionally        substituted with from 1 to 4 substituents selected from the        group consisting of: halogen, C(halogen)₃, (C₁₋₆)alkyl, OH,        O(C₁₋₆ alkyl), NH₂, and N(C₁₋₆ alkyl)₂;        R³ is selected from the group consisting of: 5-, 6- or        7-membered heterocycle having 1 to 4 heteroatoms selected from        O, N, and S, norbornane, (C₃₋₇)cycloalkyl and        (C₃₋₇)cycloalkyl-(C₁₋₆ alkyl);        M is N, CR⁴, or COR⁵, wherein R⁴ is selected from the group        consisting of: H, halogen, and (C₁₋₆ alkyl); and R⁵ is selected        from the group consisting of: H and (C₁₋₆ alkyl);        K and L is N or CH;        — represents either a single or a double bond;        Y is O;        Z is OR⁶ or NR⁶R^(6a), wherein R⁶ is selected from the group        consisting of: H, (C₁₋₆)alkyl, wherein said alkyl is optionally        substituted with from 1 to 4 substituents selected from: OH,        COOH, COO(C₁₋₆)alkyl, (C₁₋₆)alkyl, said alkyl being optionally        substituted with from 1 to 4 substituents selected from: COOH,        NHCO(C₁₋₆ alkyl), NH₂, NH(C₁₋₆ alkyl), and N(C₁₋₆ alkyl)₂;        or a salt thereof.

In a third aspect of the invention, there is provided a compound of theformula I, or a pharmaceutically acceptable salt thereof, as aninhibitor of RNA dependent RNA polymerase activity of the enzyme NS5B,encoded by HCV.

In a fourth aspect of the invention, there is provided a compound of theformula I, or a pharmaceutically acceptable salt thereof, as aninhibitor of HCV replication.

In a fifth aspect of the invention, there is provided a method oftreating or preventing HCV infection in a mammal, comprisingadministering to the mammal an effective amount of a compound of formulaI, or a pharmaceutically acceptable salt thereof.

In a sixth aspect of the invention, there is provided a pharmaceuticalcomposition for the treatment or prevention of HCV infection, comprisingan effective amount of a compound of formula I, or a pharmaceuticallyacceptable salt thereof, and a pharmaceutically acceptable carrier.

According to a specific embodiment, the pharmaceutical compositions ofthis invention comprise an additional immunomodulatory agent. Examplesof additional immunomodulatory agents include but are not limited to,α-, β-, δ- γ-, and ω-interferons.

According to an alternate embodiment, the pharmaceutical compositions ofthis invention may additionally comprise an antiviral agent. Examples ofantiviral agents include, ribavirin and amantadine.

According to another alternate embodiment, the pharmaceuticalcompositions of this invention may additionally comprise otherinhibitors of HCV polymerase.

According to yet another alternate embodiment, the pharmaceuticalcompositions of this invention may additionally comprise an inhibitor ofother targets in the HCV life cycle, such as helicase, polymerase,metalloprotease or IRES.

In a seventh aspect of the invention, there is provided a use of acompound of formula I, for the manufacture of a medicament for thetreatment of HCV infection.

In an eighth aspect of the invention, there is provided a use of acompound of formula I, as an HCV polymerase inhibitor.

In a ninth aspect of the invention, there is provided a method oftreating or preventing HCV infection in a mammal, comprisingadministering to the mammal an effective amount of a compound of formulaI, or a pharmaceutically acceptable salt thereof in combination withanother anti-HCV agent.

In a tenth aspect of the invention, there is provided an intermediate offormula (1a) or (1b):

wherein A, B, K, L, and M are as described herein and PG is H or acarboxy protecting group.

In a eleventh aspect of the invention, there is provided the use of theintermediates of formula (Ia) for producing compounds of formula (iii),

wherein A, R², B, K, L, M, and PG are as described herein, comprising:

-   a) coupling, in the presence of a metal catalyst (such as, for    example, Pd, Ni, Ru, Cu), a base and an additive (such as a    phosphine ligand, Cu salt, Li salt, ammonium salt, CsF) in an    appropriate solvent, intermediate (1a):

with R²—X, wherein R¹, R³, K, L, M and PG are as described herein and Xis (but not limited to): Sn(C₁₋₆alkyl)₃, Sn(aryl)₃, metal halide,B(OH)₂, and B(O(C₁₋₆)alkyl)₂ to produce compounds of formula (iii).

In an alternative to the eleventh aspect of the invention, there isprovided the use of intermediate (Ib) for producing compounds of formula(iii),

wherein A, R², B, K, L, M, and PG are as described herein, comprising:

-   b) coupling, in the presence of a metal catalyst (such as, for    example, Pd, Ni, Ru, Cu), a base and an additive (such as a    phosphine ligand, Cu salt, Li salt, ammonium salt, CsF) in an    appropriate solvent, intermediate (1b)

with R²—X′, wherein X′ is halide, OSO₂(C₁₋₆alkyl), OSO₂Ar, OSO₂CF₃ andthe like, and M is a metal such as Li, Sn(C₁₋₆alkyl)₃, Sn(aryl)₃,B(OH)₂, B(OC₁₋₆alkyl)₂, metal halide, to produce compounds of formula(iii).

DETAILED DESCRIPTION OF THE INVENTION Definitions

The following definitions apply unless otherwise noted:

As used herein, the terms “(C₁₋₃) alkyl”, “(C₁₄) alkyl” or “(C₁₋₆)alkyl”, either alone or in combination with another radical, areintended to mean acyclic straight or branched chain alkyl radicalscontaining up to three, four and six carbon atoms respectively. Examplesof such radicals include methyl, ethyl, propyl, butyl, hexyl,1-methylethyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl.

As used herein, the term “(C₂₋₆) alkenyl”, either alone or incombination with another radical, is intended to mean an unsaturated,acyclic straight chain radical containing two to six carbon atoms.

As used herein, the term “(C₂₋₆) alkynyl” either alone or in combinationwith another group, is intended to mean an unsaturated, acyclic straightchain sp hybridized radical containing 2 to six carbon atoms.

As used herein, the term “(C₃₋₇) cycloalkyl”, either alone or incombination with another radical, means a cycloalkyl radical containingfrom three to seven carbon atoms and includes cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl and cycloheptyl.

As used herein, the term “(C₅₋₇)cycloalkenyl”, either alone or incombination with another radical, means an unsaturated cyclic radicalcontaining five to seven carbon atoms.

As used herein, the term “carboxy protecting group” defines protectinggroups that can be used during coupling and are listed in Greene,“Protective Groups in Organic Chemistry”, John Wiley & Sons, New York(1981) and “The Peptides: Analysis, Synthesis, Biology”, Vol. 3,Academic Press, New York (1981), the disclosures of which are herebyincorporated by reference.

The α-carboxyl group of the C-terminal residue is usually protected asan ester (CPG) that can be cleaved to give the carboxylic acid.Protecting groups that can be used include: 1) alkyl esters such asmethyl, trimethylsilylethyl and t-butyl, 2) aralkyl esters such asbenzyl and substituted benzyl, or 3) esters that can be cleaved by mildbase treatment or mild reductive means such as trichloroethyl andphenacyl esters.

As used herein, the term “aryl”, or “6- or 10-membered aryl” eitheralone or in combination with another radical means aromatic radicalcontaining six or ten carbon atoms, for example phenyl or naphthyl.

As used herein the term heteroatom means O, S or N.

As used herein, the term “heterocycle”, either alone or in combinationwith another radical, means a monovalent radical derived by removal of ahydrogen from a five-, six-, or seven-membered saturated or unsaturated(including aromatic) heterocycle containing from one to four heteroatomsselected from nitrogen, oxygen and sulfur. Furthermore, “heterobicyclic”as used herein, means a heterocycle as defined above fused to one ormore other cycle, be it a heterocycle or any other cycle. Examples ofsuch heterocycles include, but are not limited to, pyrrolidine,tetrahydrofuran, thiazolidine, pyrrole, thiophene, coumarin, hydantoin,diazepine, 1H-imidazole, isoxazole, thiazole, tetrazole, piperidine,1,4-dioxane, 4-morpholine, pyridine, pyridine-N-oxide, pyrimidine,thiazolo[4,5-b]-pyridine, quinoline, or indole, or the followingheterocycles:

As used herein, the term “9- or 10-membered heterobicycle” or“heterobicycle” either alone or in combination with another radical,means a heterocycle as defined above fused to one or more other cycle,be it a heterocycle or any other cycle. Examples of such heterobicyclesinclude, but are not limited to, thiazolo[4,5-b]-pyridine, quinoline, orindole, or the following:

As used herein, the term “Het” defines a 5- or 6-membered heterocyclehaving 1 to 4 heteroatoms selected from O, N, and S, or a 9- or10-membered heterobicycle having 1 to 5 heteroatoms wherever possible,selected from O, N and S.

As used herein, the term “halo” means a halogen atom and includesfluorine, chlorine, bromine and iodine.

As used herein, the term “haloalkyl” is intended to mean an alkyl thatis described above in which each hydrogen atom may be successivelyreplaced by a halogen atom, for example CH₂Br or CF₃.

As used herein, the term “metal halide” is intended to mean any metalthat is bonded to a halogen atom for use in a metal-catalyzedcross-coupling reaction.

Examples of such metal halides include, but are not limited to, —MgCl,—CuCl, or —ZnCl and the like.

As used herein, the term “OH” refers to a hydroxyl group. It is wellknown to one skilled in the art that hydroxyl groups may be substitutedby functional group equivalents. Examples of such functional groupequivalents that are contemplated by this invention include, but are notlimited to, ethers, sulfhydryls, and primary, secondary or tertiaryamines.

As used herein, the term “SH” refers to a sulfhydryl group. It isintended within the scope of the present invention that, whenever a “SH”or “SR” group is present, it can also be substituted by any otherappropriate oxidation state such as SOR, SO₂R, or SO₃R.

It is intended that the term “substituted” when applied in conjunctionwith a radical having more than one moiety such as C₁₋₆alkyl-aryl, orC₁₋₆alkyl-Het, such substitution applies to both moieties i.e. both thealkyl and aryl or Het moieties can be substituted with the definedsubstituents.

As used herein, the term “COOH” refers to a carboxylic acid group. It iswell known to one skilled in the art that carboxylic acid groups may besubstituted by functional group equivalents. Examples of such functionalgroup equivalents that are contemplated by this invention include, butare not limited to, esters, amides, boronic acids or tetrazole.

As used herein, the term “functional group equivalent” is intended tomean an element or a substituted derivative thereof, that is replaceableby another element that has similar electronic, hybridization or bondingproperties.

As used herein, the term “metal catalyst” is intended to mean a metalsuch as palladium (0) or palladium (2) that is bonded to a leaving groupfor use in a cross-coupling reaction. Examples of such palladiumcatalysts include, but are not limited to, Pd(Ph₃)₄, Pd/C, Pd(OAc)₂,PdCl₂, and the like. Alternative metals that can catalyze cross-couplingreactions include, but are not limited to: Ni(acac)₂, Ni(OAc)₂, orNiCl₂.

As used herein, the term “derivative” is intended to mean “detectablelabel”, “affinity tag” or “photoreactive group”. The term “detectablelabel” refers to any group that may be linked to the polymerase or to acompound of the present invention such that when the compound isassociated with the polymerase target, such label allows recognitioneither directly or indirectly of the compound such that it can bedetected, measured and quantified. Examples of such “labels” areintended to include, but are not limited to, fluorescent labels,chemiluminescent labels, colorimetric labels, enzymatic markers,radioactive isotopes and affinity tags such as biotin. Such labels areattached to the compound or to the polymerase by well known methods.

The term “affinity tag” means a ligand (that is linked to the polymeraseor to a compound of the present invention) whose strong affinity for areceptor can be used to extract from a solution the entity to which theligand is attached. Examples of such ligands include biotin or aderivative thereof, a histidine polypeptide, a polyarginine, an amylosesugar moiety or a defined epitope recognizable by a specific antibody.Such affinity tags are attached to the compound or to the polymerase bywell-known methods.

The term “photoreactive group” means a group that is transformed, uponactivation by light, from an inert group to a reactive species, such asa free radical. Examples of such groups include, but are not limited to,benzophenones, azides, and the like.

As used herein, the term “pharmaceutically acceptable salt” includesthose derived from pharmaceutically acceptable bases and is non-toxic.Examples of suitable bases include choline, ethanolamine andethylenediamine. Na⁺, K⁺, and Ca⁺⁺ salts are also contemplated to bewithin the scope of the invention (also see Pharmaceutical salts, Birge,S. M. et al., J. Pharm. Sci., (1977), 66, 1-19, incorporated herein byreference).

Preferred Embodiments

A:

Preferably, compounds of the present invention have the followingformula (II):

wherein, preferably, A is O, S, or NR¹.

Preferably, A is NR¹.

Preferably, compounds of the present invention have the followingformula (III):

wherein, preferably, B is NR³.

With respect to compounds of formula (II) and (III), preferably, M, Kand L is CH or N. More preferably, K and L is CH.

More preferably, compounds of the present invention have the followingformulae:

R¹:

Preferably R¹ is selected from the group consisting of: H or(C₁₋₆)alkyl. More preferably, R¹ is H, CH₃, isopropyl, or isobutyl. Evenmore preferably, R¹ is H or CH₃. Most preferably, R¹ is CH₃.

R²:

Preferably, R² is selected from: H, halogen, (C₂₋₆)alkenyl,(C₅₋₇)cycloalkenyl, 6 or 10-membered aryl or Het; wherein (C₂₋₆)alkenyl,(C₅₋₇)cycloalkenyl, aryl or Het is optionally substituted with R²⁰,wherein R²⁰ is defined as:

-   -   1 to 4 substituents selected from: halogen, NO₂, cyano, azido,        C(═NH)NH₂, C(═NH)NH(C₁₋₆)alkyl or C(═NH)NHCO(C₁₋₆)alkyl; or    -   1 to 4 substituents selected from:    -   a) (C₁₋₆) alkyl or haloalkyl, (C₃₋₇)cycloalkyl, (C₂₋₆)alkenyl,        (C₂₋₈)alkynyl, (C₁₋₆) alkyl-(C₃₋₇)cycloalkyl, all of which        optionally substituted with R¹⁵⁰;    -   b) OR¹⁰⁴ wherein R¹⁰⁴ is H, (C₁₋₆alkyl), (C₃₋₇)cycloalkyl, or        (C₁₋₆)alkyl-(C₃₋₇)cycloalkyl, aryl, Het, (C₁₋₆alkyl)aryl or        (C₁₋₆alkyl)Het, said alkyl, cycloalkyl, aryl, Het,        (C₁₋₆alkyl)aryl or (C₁₋₆alkyl)Het being optionally substituted        with R¹⁵⁰;    -   c) OCOR¹⁰⁵ wherein R¹⁰⁵ is (C₁₋₆)alkyl, (C₃₋₇)cycloalkyl,        (C₁₋₆)alkyl-(C₃₋₇)cycloalkyl, Het, (C₁₋₆alkyl)aryl or        (C₁₋₆alkyl)Het, said alkyl, cycloalkyl, aryl, Het,        (C₁₋₆alkyl)aryl or (C₁₋₆alkyl)Het being optionally substituted        with R¹⁵⁰;    -   d) SR¹⁰⁸, SO₂N(R¹⁰⁸)₂ or SO₂N(R¹⁰⁸)C(O)R¹⁰⁸ wherein each R¹⁰⁸ is        independently H, (C₁₋₆)alkyl, (C₃₋₇)cycloalkyl or        (C₁₋₆)alkyl-(C₃₋₇)cycloalkyl, aryl, Het, (C₁₋₆alkyl)aryl or        (C₁₋₆alkyl)Het or both R¹⁰⁸ are covalently bonded together and        to the nitrogen to which they are attached to form a 5, 6 or        7-membered saturated heterocycle, said alkyl, cycloalkyl, aryl,        Het, (C₁₋₆alkyl)aryl or (C₁₋₆alkyl)Het or heterocycle being        optionally substituted with R¹⁵⁰;    -   e) NR¹¹¹R¹¹² wherein R¹¹¹ is H, (C₁₋₆)alkyl, (C₃₋₇)cycloalkyl or        (C₁₋₆)alkyl-(C₃₋₇)cycloalkyl, aryl, Het, (C₁₋₆alkyl)aryl or        (C₁₋₆alkyl)Het, and R¹¹² is H, CN, (C₁₋₆)alkyl, (C₃₋₇)cycloalkyl        or (C₁₋₆)alkyl-(C₃₋₇)cycloalkyl, aryl, Het, (C₁₋₆alkyl)aryl,        (C₁₋₆alkyl)Het, COOR¹¹⁵ or SO₂R¹¹⁵ wherein R¹¹⁵ is (C₁₋₆)alkyl,        (C₃₋₇)cycloalkyl, or (C₁₋₆)alkyl-(C₃₋₇)cycloalkyl, aryl, Het,        (C₁₋₆alkyl)aryl or (C₁₋₆alkyl)Het, or both R¹¹¹ and R¹¹² are        covalently bonded together and to the nitrogen to which they are        attached to form a 5, 6 or 7-membered saturated heterocycle,        said alkyl, cycloalkyl, aryl, Het, (C₁₋₆alkyl)aryl or        (C₁₋₆alkyl)Het, or heterocycle being optionally substituted with        R¹⁵⁰;    -   f) NR¹¹⁶COR¹¹⁷ wherein R¹¹⁶ and R¹¹⁷ is each H, (C₁₋₆)alkyl,        (C₃₋₇)cycloalkyl, (C₁₋₆)alkyl-(C₃₋₇)cycloalkyl, aryl, Het,        (C₁₋₆alkyl)aryl or (C₁₋₆alkyl)Het, said (C₁₋₆)alkyl,        (C₃₋₇)cycloalkyl, (C₁₋₆)alkyl-(C₃₋₇)cycloalkyl, aryl, Het,        (C₁₋₆alkyl)aryl or (C₁₋₆alkyl)Het being optionally substituted        with R¹⁵⁰;    -   g) NR¹⁸CONR¹¹⁹R¹²⁰, wherein R¹¹⁸R¹¹⁹ and R¹²⁰ is each H,        (C₁₋₆)alkyl, (C₃₋₇)cycloalkyl, (C₁₋₆)alkyl-(C₃₋₇)cycloalkyl,        aryl, Het, (C₁₋₆alkyl)aryl or (C₁₋₆alkyl)Het, or R¹¹⁸ is        covalently bonded to R¹¹⁹ and to the nitrogen to which they are        attached to form a 5, 6 or 7-membered saturated heterocycle;    -   or R¹¹⁹ and R¹²⁰ are covalently bonded together and to the        nitrogen to which they are attached to form a 5, 6 or 7-membered        saturated heterocycle;    -   said alkyl, cycloalkyl, (C₁₋₆)alkyl-(C₃₋₇)cycloalkyl, aryl, Het,        (C₁₋₆alkyl)aryl or (C₁₋₆alkyl)Het or heterocycle being        optionally substituted with R¹⁵⁰;    -   h) NR¹²¹COCOR¹²² wherein R¹²¹ and R¹²² is each H, (C₁₋₆)alkyl,        (C₃₋₇)cycloalkyl, (C₁₋₆)alkyl-(C₃₋₇)cycloalkyl, a 6- or        10-membered aryl, Het, (C₁₋₆alkyl)aryl or (C₁₋₆alkyl)Het, said        alkyl, cycloalkyl, alkyl-cycloalkyl, aryl, Het, (C₁₋₆alkyl)aryl        or (C₁₋₆alkyl)Het being optionally substituted with R¹⁵⁰; or        R¹²² is OR¹²³ or N(R¹²⁴)₂ wherein R¹²³ and each R¹²⁴ is        independently H (C₁₋₆alkyl), (C₃₋₇)cycloalkyl, or        (C₁₋₆)alkyl-(C₃₋₇)cycloalkyl, aryl, Het, (C₁₋₆alkyl)aryl or        (C₁₋₆alkyl)Het, or R¹²⁴ is OH or O(C₁₋₆alkyl) or both R¹²⁴ are        covalently bonded together to form a 5, 6 or 7-membered        saturated heterocycle, said alkyl, cycloalkyl, alkyl-cycloalkyl,        aryl, Het, (C₁₋₆alkyl)aryl or (C₁₋₆alkyl)Het and heterocycle        being optionally substituted with R¹⁵⁰;    -   i) COR¹²⁷ wherein R¹²⁷ is H, (C₁₋₆)alkyl, (C₃₋₇)cycloalkyl or        (C₁₋₆)alkyl-(C₃₋₇)cycloalkyl, aryl, Het, (C₁₋₆alkyl)aryl or        (C₁₋₆alkyl)Het, said alkyl, cycloalkyl, aryl, Het,        (C₁₋₆alkyl)aryl or (C₁₋₆alkyl)Het being optionally substituted        with R¹⁵⁰;    -   j) COOR¹²⁸ wherein R¹²⁸ is H, (C₁₋₆)alkyl, (C₃₋₇)cycloalkyl, or        (C₁₋₆)alkyl-(C₃₋₇)cycloalkyl, aryl, Het, (C₁₋₆alkyl)aryl or        (C₁₋₆alkyl)Het, said (C₁₋₆)alkyl, (C₃₋₇)cycloalkyl, or        (C₁₋₆)alkyl-(C₃₋₇)cycloalkyl, aryl, Het, (C₁₋₆alkyl)aryl and        (C₁₋₆alkyl)Het being optionally substituted with R¹⁵⁰;    -   k) CONR¹²⁹R¹³⁰ wherein R¹²⁹ and R¹³⁰ are independently H,        (C₁₋₆)alkyl (C₃₋₇)cycloalkyl, (C₁₋₆)alkyl-(C₃₋₇)cycloalkyl,        aryl, Het, (C₁₋₆alkyl)aryl or (C₁₋₆alkyl)Het, or both R¹²⁹ and        R¹³⁰ are covalently bonded together and to the nitrogen to which        they are attached to form a 5, 6 or 7-membered saturated        heterocycle, said alkyl, cycloalkyl, alkyl-cycloalkyl, aryl,        Het, (C₁₋₆alkyl)aryl, (C₁₋₆alkyl)Het and heterocycle being        optionally substituted with R¹⁵⁰,    -   l) aryl, Het, (C₁₋₆alkyl)aryl or (C₁₋₆alkyl)Het, all of which        being optionally substituted with R¹⁵⁰;        -   wherein R¹⁵⁰ is preferably:        -   1 to 3 substituents selected from: halogen, NO₂, cyano or            azido; or        -   1 to 3 substituents selected from:        -   a) (C₁₋₆) alkyl or haloalkyl, (C₃₋₇)cycloalkyl,            (C₂₋₆)alkenyl, (C₂₋₈)alkynyl, (C₁₋₆) alkyl-(C₃₋₇)cycloalkyl,            all of which optionally substituted with R¹⁶⁰;        -   b) OR¹⁰⁴ wherein R¹⁰⁴ is H, (C₁₋₆alkyl) or (C₃₋₇)cycloalkyl,            said alkyl or cycloalkyl optionally substituted with R¹⁶⁰;        -   d) SR¹⁰⁸, SO₂N(R¹⁰⁸)₂ or SO₂N(R¹⁰⁸)C(O)R¹⁰⁸ wherein each            R¹⁰⁸ is independently H, (C₁₋₆)alkyl, (C₃₋₇)cycloalkyl or            (C₁₋₆)alkyl-(C₃₋₇)cycloalkyl, aryl, Het, or both R¹⁰⁸ are            covalently bonded together and to the nitrogen to which they            are attached to form a 5, 6 or 7-membered saturated            heterocycle, said alkyl, cycloalkyl, aryl, Het and            heterocycle being optionally substituted with R¹⁶⁰;        -   e) NR¹¹¹R¹¹² wherein R¹¹¹ is H, (C₁₋₆)alkyl, or            (C₃₋₇)cycloalkyl, and R¹¹² is H, (C₁₋₆)alkyl or            (C₃₋₇)cycloalkyl, COOR¹¹⁵ or SO₂R¹¹⁵ wherein R¹¹⁵ is            (C₁₋₆)alkyl or (C₃₋₇)cycloalkyl, or both R¹¹¹ and R¹¹² are            covalently bonded together and to the nitrogen to which they            are attached to form a 5, 6 or 7-membered saturated            heterocycle, said alkyl, cycloalkyl and heterocycle being            optionally substituted with R¹⁶⁰;        -   f) NR¹¹⁶COR¹¹⁷ wherein R¹¹⁶ and R¹¹⁷ is each H, (C₁₋₆)alkyl            or (C₃₋₇)cycloalkyl said (C₁₋₆)alkyl and (C₃₋₇)cycloalkyl            being optionally substituted with R¹⁶⁰;        -   g) NR¹¹⁸CONR¹¹⁹R¹²⁰ wherein R¹¹⁸, R¹¹⁹ and R¹²⁰ is each H,            (C₁₋₆)alkyl or (C₃₋₇)cycloalkyl, or R¹¹⁸ is covalently            bonded to R¹¹⁹ and to the nitrogen to which they are            attached to form a 5, 6 or 7-membered saturated heterocycle;        -   or R¹¹⁹ and R¹²⁰ are covalently bonded together and to the            nitrogen to which they are attached to form a 5, 6 or            7-membered saturated heterocycle;        -   said alkyl, cycloalkyl, and heterocycle being optionally            substituted with R¹⁶⁰;        -   h) NR¹²¹COCOR¹²² wherein R¹²¹ is H, (C₁₋₆)alkyl or            (C₃₋₇)cycloalkyl, said alkyl and cycloalkyl being optionally            substituted with R¹⁶⁰;        -   or R¹²² is OR¹²³ or N(R¹²⁴)₂ wherein R¹²³ and each R¹²⁴ is            independently H, (C₁₋₆alkyl) or (C₃₋₇)cycloalkyl, or both            R¹²⁴ are covalently bonded together to form a 5, 6 or            7-membered saturated heterocycle, said alkyl, cycloalkyl and            heterocycle being optionally substituted with R¹⁶⁰;        -   i) COR¹²⁷ wherein R¹²⁷ is H, (C₁₋₆)alkyl or            (C₃₋₇)cycloalkyl, said alkyl and cycloalkyl being optionally            substituted with R¹⁶⁰;        -   j) COOR¹²⁸ wherein R¹²⁸ is H, (C₁₋₆)alkyl or            (C₃₋₇)cycloalkyl, said (C₁₋₆)alkyl and (C₃₋₇)cycloalkyl            being optionally substituted with R¹⁶⁰; and        -   k) CONR¹²⁹R¹³⁰ wherein R¹²⁹ and R¹³⁰ are independently H,            (C₁₋₆)alkyl or (C₃₋₇)cycloalkyl, or both R¹²⁹ and R¹³⁰ are            covalently bonded together and to the nitrogen to which they            are attached to form a 5, 6 or 7-membered saturated            heterocycle, said alkyl, cycloalkyl and heterocycle being            optionally substituted with R¹⁶⁰;            -   wherein R¹⁶⁰ is defined as 1 or 2 substituents selected                from:            -   halogen, CN, C₁₋₆alkyl, haloalkyl, COOR¹⁶¹, OR¹⁶¹,                N(R¹⁶²)₂, SO₂N(R¹⁶²)₂, NR¹⁶²COR¹⁶² or CON(R¹⁶²)₂,                wherein R¹⁶¹ and each R¹⁶² is independently H,                (C₁₋₆)alkyl, (C₃₋₇)cycloalkyl or                (C₁₋₆)alkyl-(C₃₋₇)cycloalkyl; or both R¹⁶² are                covalently bonded together and to the nitrogen to which                they are attached to form a 5, 6 or 7-membered saturated                heterocycle.

More preferably, R² is selected from: aryl or Het, each optionallymonosubstituted or disubstituted with substituents selected from thegroup consisting of: halogen, haloalkyl, N₃, or

-   -   a) (C₁₋₆)alkyl optionally substituted with OH, O(C₁₋₆)alkyl or        SO₂(C₁₋₆ alkyl);    -   b) (C₁₋₆)alkoxy;    -   e) NR¹¹¹R¹¹² wherein both R¹¹¹ and R¹¹² are independently H,        (C₁₋₆)alkyl, (C₃₋₇)cycloalkyl, or R¹¹² is 6- or 10-membered        aryl, Het, (C₁₋₆)alkyl-aryl or (C₁₋₆)alkyl-Het; or both R¹¹¹ and        R¹¹² are covalently bonded together and to the nitrogen to which        they are attached to form a nitrogen-containing heterocycle,        each of said alkyl, cycloalkyl, aryl, Het, alkyl-aryl or        alkyl-Het; being optionally substituted with halogen or:        -   OR¹⁶¹ or N(R¹⁶²)₂, wherein R¹⁶¹ and each R¹⁶² is            independently H, (C₁₋₆)alkyl, or both R¹⁶² are covalently            bonded together and to the nitrogen to which they are            attached to form a nitrogen-containing heterocycle;    -   f) NHCOR¹¹⁷ wherein R¹¹⁷ is (C₁₋₆)alkyl, O(C₁₋₆)alkyl or        O(C₃₋₇)cycloalkyl;    -   i) CO-aryl; and    -   k) CONH₂, CONH(C₁₋₆alkyl), CON(C₁₋₆alkyl)₂, CONH-aryl, or        CONHC₁₋₆alkyl-aryl.

Still, more preferably, R² is aryl or Het, each optionallymonosubstituted or disubstituted with substituents selected from thegroup consisting of: halogen, haloalkyl, or

-   -   a) (C₁₋₆)alkyl optionally substituted with OH, O(C₁₋₆)alkyl or        SO₂(C₁₋₆alkyl);    -   b) (C₁₋₆)alkoxy; and    -   e) NR¹¹¹R¹¹² wherein both R¹¹¹ and R¹¹² are independently H,        (C₁₋₆)alkyl, (C₃₋₇)cycloalkyl, or R¹¹² is 6- or 10-membered        aryl, Het, (C₁₋₆)alkyl-aryl or (C₁₋₆)alkyl-Het; or both R¹¹¹ and        R¹¹² are covalently bonded together and to the nitrogen to which        they are attached to form a nitrogen-containing heterocycle,        each of said alkyl, cycloalkyl, aryl, Het, alkyl-aryl or        alkyl-Het; or being optionally substituted with halogen or:        -   OR¹⁶¹ or N(R¹⁶²)₂, wherein R¹⁶¹ and each R¹⁶² is            independently H, (C₁₋₆)alkyl, or both R¹⁶² are covalently            bonded together and to the nitrogen to which they are            attached to form a nitrogen-containing heterocycle.

Even more preferably, R² is phenyl or a heterocycle selected from:

all of which optionally substituted as defined above.

Even more preferably, R² is selected from the group consisting of:

Still more preferably, R² is selected from:

Most preferably, R² is selected from:

R³:

Preferably, R³ is selected from (C₃₋₇)cycloalkyl, (C₃₋₇)cycloalkenyl,(C₆₋₁₀)bicycloalkyl, (C₆₋₁₀)bicycloalkenyl, 6- or 10-membered aryl, orHet. More preferably, R³ is (C₃₋₇)cycloalkyl. Most preferably, R³ iscyclopentyl, or cyclohexyl.

Y:

Preferably Y¹ is O.

Z:

Preferably, Z is OR⁶, wherein R⁶ is H, (C₁₋₆)alkyl being optionallysubstituted with: halo, hydroxy, carboxy, amino, C₁₋₆ alkoxy,C₁₋₆alkoxycarbonyl, and C₁₋₆ alkylamino; or R⁶ is C₁₋₆ alkylaryloptionally substituted with: halogen, cyano, nitro, C₁₋₆ alkyl,C₁₋₆haloalkyl, C₁₋₆alkanoyl, —(CH₂)₁₋₆—COOR⁷, —(CH₂)₁₋₆—CONR⁷R⁸,—(CH₂)₁₋₆—NR⁷R⁸, —(CH₂)₁₋₆—NR⁷COR⁸, —(CH₂)₁₋₆—NHSO₂R⁷, —(CH₂)₁₋₆—OR⁷,—(CH₂)₁₋₆—SR⁷, —(CH₂)₁₋₆—SO₂R⁷, and —(CH₂)₁₋₆—SO₂NR⁷R⁸, wherein each R⁷and each R⁸ is H or C₁₋₆ alkyl,

or Z is NR⁹R¹⁰ wherein each of R⁹ and R¹⁰ is selected from: H,C₁₋₆alkoxy, or C₁₋₆alkyl optionally substituted with halo, hydroxy,carboxy, amino, C₁₋₆ alkoxy, C₁₋₆alkoxycarbonyl, and C₁₋₆ alkylamino;

More preferably, Z is OH or O(C₁₋₆alkyl) or Z is NR⁹R¹⁰ wherein R⁹ ispreferably H and R¹⁰ is preferably H or C₁₋₆alkyl.

Most preferably, Z is OH.

Specific Embodiments

Included within the scope of this invention are all compounds of formulaI as presented in Tables 1 and 2.

Polymerase Activity

The ability of the compounds of formula (I) to inhibit RNA synthesis bythe RNA dependent RNA polymerase of HCV can be demonstrated by any assaycapable of measuring RNA dependent RNA polymerase activity. A suitableassay is described in the examples.

Specificity for RNA Dependent RNA Polymerase Activity

To demonstrate that the compounds of the invention act by specificinhibition of HCV polymerase, the compounds may be tested for inhibitoryactivity in a DNA dependent RNA polymerase assay.

When a compound of formula (I), or one of its therapeutically acceptablesalts, is employed as an antiviral agent, it is administered orally,topically or systemically to mammals, e.g. humans, rabbits or mice, in avehicle comprising one or more pharmaceutically acceptable carriers, theproportion of which is determined by the solubility and chemical natureof the compound, chosen route of administration and standard biologicalpractice.

For oral administration, the compound or a therapeutically acceptablesalt thereof can be formulated in unit dosage forms such as capsules ortablets each containing a predetermined amount of the active ingredient,ranging from about 25 to 500 mg, in a pharmaceutically acceptablecarrier.

For topical administration, the compound can be formulated inpharmaceutically accepted vehicles containing 0.1 to 5 percent,preferably 0.5 to 5 percent, of the active agent. Such formulations canbe in the form of a solution, cream or lotion.

For parenteral administration, the compound of formula (I) isadministered by either intravenous, subcutaneous or intramuscularinjection, in compositions with pharmaceutically acceptable vehicles orcarriers. For administration by injection, it is preferred to use thecompounds in solution in a sterile aqueous vehicle which may alsocontain other solutes such as buffers or preservatives as well assufficient quantities of pharmaceutically acceptable salts or of glucoseto make the solution isotonic.

Suitable vehicles or carriers for the above noted formulations aredescribed in pharmaceutical texts, e.g. in “Remington's The Science andPractice of Pharmacy”, 19th ed., Mack Publishing Company, Easton, Pa.,1995, or in “Pharmaceutical Dosage Forms And Drugs Delivery Systems”,6th ed., H. C. Ansel et al., Eds., Williams & Wilkins, Baltimore, Md.,1995.

The dosage of the compound will vary with the form of administration andthe particular active agent chosen. Furthermore, it will vary with theparticular host under treatment. Generally, treatment is initiated withsmall increments until the optimum effect under the circumstance isreached. In general, the compound of formula I is most desirablyadministered at a concentration level that will generally affordantivirally effective results without causing any harmful or deleteriousside effects.

For oral administration, the compound or a therapeutically acceptablesalt is administered in the range of 10 to 200 mg per kilogram of bodyweight per day, with a preferred range of 25 to 150 mg per kilogram.

For systemic administration, the compound of formula (I) is administeredat a dosage of 10 mg to 150 mg per kilogram of body weight per day,although the aforementioned variations will occur. A dosage level thatis in the range of from about 10 mg to 100 mg per kilogram of bodyweight per day is most desirably employed in order to achieve effectiveresults.

When the compositions of this invention comprise a combination of acompound of formula I and one or more additional therapeutic orprophylactic agent, both the compound and the additional agent should bepresent at dosage levels of between about 10 to 100%, and morepreferably between about 10 and 80% of the dosage normally administeredin a monotherapy regimen.

When these compounds or their pharmaceutically acceptable salts areformulated together with a pharmaceutically acceptable carrier, theresulting composition may be administered in vivo to mammals, such asman, to inhibit HCV polymerase or to treat or prevent HCV virusinfection. Such treatment may also be achieved using the compounds ofthis invention in combination with agents which include, but are notlimited to: immunomodulatory agents, such as α-, β-, or γ-interferons;other antiviral agents such as ribavirin, amantadine; other inhibitorsof HCV NS5B polymerase; inhibitors of other targets in the HCV lifecycle, which include but not limited to, helicase, NS2/3 protease, NS3protease, or internal ribosome entry site (IRES); or combinationsthereof. The additional agents may be combined with the compounds ofthis invention to create a single dosage form. Alternatively theseadditional agents may be separately administered to a mammal as part ofa multiple dosage form.

Methodology and Synthesis

Indole derivatives or analogs according to the present invention can beprepared from known monocyclic aromatic compounds by adapting knownliterature sequences such as those described by J. W. Ellingboe et al.(Tet. Lett. 1997, 38, 7963) and S. Cacchi et al. (Tet. Lett. 1992, 33,3915). Scheme 1, shown below wherein R¹, R², R³, R⁶, K, L, and M are asdescribed herein illustrate how these procedures can be adapted to thesynthesis of compounds of formula 1 of this invention.

In carrying out the route illustrated in Scheme 1, a suitably protectedform of 3-trifluoroacetamido-4-iodobenzoic acid I(i) is reacted with analkyne I(ii) in the presence of a metal catalyst (e.g. a palladium metalcomplex such as PdCl₂(PPh₃)₂, Pd₂ dba₃, Pd(PPh₃)₄ and the like), a base(Et₃N, DIEA and the like or an inorganic basic salt including metalcarbonates, fluorides and phosphates), and optionally in the presence ofan additional phosphine ligand (triaryl or heteroarylphosphine, dppe,dppf, dppp and the like). Suitable solvents for this reaction includeDMF, dioxane, THF, DME, toluene, MeCN, DMA and the like at temperaturesranging from 20° C. to 170° C., or alternatively without solvent byheating the components together. Alternatively, the cross-couplingreaction can be carried out on a suitably protected form of3-amino-4-iodobenzoate and the amino group can be trifluoroacetylated inthe subsequent step as described by J. W. Ellingboe et al. (Tet. Lett.1997, 38, 7963).

Reaction of the above diarylalkynes I(iii) with an enol triflate undercross-coupling conditions similar to those described above gives afterhydrogenation of the douple bond, indole derivatives I(iv). Enoltriflates are known and can be prepared from the corresponding ketonesby following known literature methods (for example, cyclohexene triflatecan be prepared from cyclohexanone, triflic anhydride and a hinderedorganic base such as 2,6-di-tert-butyl-4-methylpyridine). Thehydrogenation of the double bond originally present in R¹ can be carriedout with hydrogen gas or a hydrogen donor (ammonium formate, formic acidand the like) in the presence of a metal catalyst (preferably Pd) in asuitable solvent (lower alkyl alcohols, THF etc.).

Finally, following hydrolysis of the ester protecting group in I(iv),the resulting 6-carboxyindole derivative I(v) is converted to compoundsof formula 1 by coupling with the appropriate amine of formula H₂N—R⁶.Condensation of the 6-indolecarboxylic acid with amines H₂N—R⁶ can beaccomplished using standard amide bond forming reagents such as TBTU,HATU, BOP, BroP, EDAC, DCC, isobutyl chloroformate and the like, or byactivation of the carboxyl group by conversion to the corresponding acidchloride prior to condensation with an amine. Any remaining protectinggroup is removed following this step to give compounds of formula 1.

Alternatively, compounds of formula 1 can be prepared by elaborationfrom a pre-existing indole core by following adaptations of literatureprocedures as described, for example, by P. Gharagozloo et al.(Tetrahedron 1996, 52, 10185) or K. Freter (J. Org. Chem. 1975, 40,2525). Such a methodology is illustrated in Scheme 2:

In carrying the route illustrated in Scheme 2, commercially available6-indolecarboxylic acid 2(i), which can also be prepared according tothe method of S. Kamiya et al. (Chem. Pharm. Bull. 1995, 43, 1692) isused as the starting material. The indole 2(i) is reacted with a ketone2(ii) under basic or acidic aldol-type conditions. Suitable conditionsto affect this condensation include strong bases such as alkali metalhydroxides, alkoxides and hydrides in solvents such as lower alkylalcohols (MeOH, EtOH, tertBuOH etc.), THF, dioxane, DMF, DMSO, DMA andthe like at reaction temperature ranging from −20° C. to 120° C.Alternatively, the condensation can be carried out under acid conditionsusing organic or mineral acids or both. Appropriate conditions includemixtures of AcOH and aqueous phosphoric acid at temperatures rangingfrom 15° C. to 120° C.

Following protection of the carboxylic acid group in the form of anester (usually lower alkyl) using known methods, the indole nitrogen canbe alkylated with R³ if desired. Reaction conditions to alkylate thenitrogen of an indole derivative are well known to those skilled in theart and include the use of strong bases such as alkali metal hydrides,hydroxides, amides, alkoxides and alkylmetals, in the appropriatesolvent (such as THF, dioxane, DME, DMF. MeCN, DMSO, alcohols and thelike) at temperatures ranging from −78° C. to 140° C. An electrophilicform of R³ is used for the alkylation of the indole anion. Suchelectrophilic species include iodides, bromides, chlorides and sulfonateesters (mesylates, tosylate, brosylate or triflate).

Halogenation (usually bromination, but also iodination) of the2-position of the indole 2(iv) gives 2(v). Suitable halogenating agentsinclude, for example, elemental bromine, N-bromosuccinimide, pyridinetribromide, dibromohydantoin and the corresponding iodo derivatives.Suitable solvents for this reaction are inert to reactive halogenatingagents and include for example hydrocarbons, chlorinated hydrocarbons(DCM, CCl₄, CHCl₃), ethers (THF, DME, dioxane), acetic acid, ethylacetate, IPA, and mixtures of these solvents. Reaction temperatureranges from −40° C. to 100° C. A method of choice to carry out thebromination of indoles as shown in Scheme 2 was described by L. Chu(Tet. Lett. 1997, 38, 3871).

The 2-bromoindole derivatives 2(v) can be converted directly to fullysubstituted key intermediates I(v) through a cross-coupling reactionwith aryl or heteroaryl boronic acids, boronate esters ortrialkylstannane derivatives. These boron or tin organometallic speciesare from commercial sources or can be prepared by standard literatureprocedures. Cross-coupling with organoboron reagents can be carried outby any variations of the Suzuki cross-coupling reaction reported in theliterature. This usually involves the use of a transition metal catalyst(usually Pd°), triaryl or triheteroarylphosphine ligands, an additivesuch as an inorganic chloride (e.g. LiCl), and a base (usually anaqueous inorganic base such as sodium or potassium carbonate orphosphate). The reaction is usually carried out in an alcoholic solvent(EtOH), DME, toluene, THF and the like at temperatures ranging from 25°C. to 140° C.

Cross-coupling with tin reagents can be carried out by any variations ofthe Stille cross-coupling reaction reported in the literature. Thisusually involves the use of a transition metal catalyst (usually Pd°),triaryl or triheteroaryl phosphine ligands, and an additive such as aninorganic chloride (e.g. LiCl) or iodide (e.g. CuI). Suitable solventsfor this reaction include toluene, DMF, THF, DME and the like attemperatures ranging from 25° C. to 140° C. Intermediate I(v) is thenconverted to compounds of formula 1 as described for Scheme 1.

Alternatively, the 2-bromoindole intermediate 2(v) can betrans-metallated to an organotin species (or organozinc) and used inStille-type cross-coupling reactions under conditions described above.In this case, aromatic and heteroaromatic halides (chlorides, bromides,iodides) or triflates are used to introduce R². The conversion of2-bromoindole derivatives 2(v) to the corresponding organotin species2(vi) is carried out via initial low-temperature (usually −78° to −30°C.) halogen-metal exchange using an alkyllithium reagent (e.g. nBuLi ortert-BuLi) or using lithium metal. The transient 2-lithioindole speciesis then trapped with a trialkyltin halide (e.g. nBu₃SnCl or Me₃SnCl).Alternatively, the lithioindole intermediate can be trapped with zincchloride to form the corresponding organozincate which can also undergotransition metal-catalyzed cross-coupling with aromatic andheteroaromatic halides or triflates as described, for example, by M.Rowley (J. Med. Chem. 2001, 44, 1603).

The present invention also encompasses compounds of formula 1 where thecarboxylic group is in the 5-position of the indole system. Thesynthesis of such compounds is based on adaptation of literatureprocedures and is depicted in Scheme 3:

In carrying out the synthetic route illustrated in Scheme 3, ethyl4-acetamido-3-iodobenzoate 3(i) undergoes metal catalyzed cross-couplingwith an alkyne 3(ii) to give a 2,3-disubstituted-5-indolecarboxylate3(iii) according to an adaptation of a procedure described by A.Bedeschi et al. (Tet. Lett. 1997, 38, 2307). The indole derivative3(iii) is then alkylated on nitrogen with electrophilic R¹ groups(halides, sulfonate esters) under the action of a base such as alkalimetal hydroxides, fluorides, hydrides amides, alkyllithium, phosphabasesand the like, to give 3(iv). Suitable solvents for this alkylationinclude DMF, DMA, DMSO, MeCN, THF, dioxane, DME and the like. Followingsaponification of the ester group with an alkaline solution, theresulting 5-indolecarboxylic acid derivative 3(v) is coupled to H₂N—R⁶using an amide bond forming reagent as described previously (Scheme 1),to give compounds of formula I.

EXAMPLES

The present invention is illustrated in further detail by the followingnon-limiting examples. All reactions were performed in a nitrogen orargon atmosphere. Temperatures are given in degrees Celsius. Flashchromatography was performed on silica gel. Solution percentages orratios express a volume to volume relationship, unless stated otherwise.Mass spectral analyses were recorded using electrospray massspectrometry. Abbreviations or symbols used herein include:

DIEA: diisopropylethylamine;

DMAP: 4-(dimethylamino)pyridine;

DMSO: dimethylsulfoxide;

DMF: N,N-dimethylformamide;

Et: ethyl;

EtOAc: ethyl acetate;

Et₂O: diethyl ether;

HPLC: high performance liquid chromatography;

^(i)Pr: isopropyl

Me: methyl;

MeOH: Methanol;

MeCN: acetonitrile;

Ph: phenyl;

TBE: tris-borate-EDTA;

TBTU: 2-(1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumtetrafluoroborate;

TFA: trifluoroacetic acid;

TFAA: trifluoroacetic anhydride;

THF: tetrahydrofuran;

MS (ES): electrospray mass spectrometry;

PFU: plaque forming units;

DEPC: diethyl pyrocarbonate;

DTT: dithiothreitol

EDTA: ethylenediaminetetraacetate

HATU: O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate

BOP: benzotriazole-1-yloxy-tris(dimethylamino)phosphoniumhexafluorophosphate

EDAC: see ECD

DCC: 1,3-Dicyclohexyl carbodiimide

HOBt: 1-Hydroxybenzotriazole

ES⁺: electro spray (positive ionization)

ES⁻: electro spray (negative ionization)

DCM: dichloromethane

TBME: tert-butylmethyl ether

TLC: thin layer chromatography

AcOH: acetic acid

EtOH: ethanol

DBU: 1,8-diazabicyclo[5.4.0]under-7-ene

BOC: tert-butyloxycarbonyl

Cbz: carbobenzyloxy carbonyl

^(i)PrOH: isopropanol

NMP: N-methylpyrrolidone

EDC: 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride

RNAsin: A ribonuclease inhibitor marketed by Promega Corporation

Tris: 2-amino-2-hydroxymethyl-1,3-propanediol

UMP: uridine 5′-monophosphate

UTP: uridine 5′-triphosphate

IPA: isopropyl acetate

Examples 1-22 illustrate methods of synthesis of representativecompounds of this invention.

Example 1

Methyl 3-amino-4-iodobenzoate

3-Amino-4-iodobenzoic acid (13.35 g, 50.8 mmol) was added to MeOH (150mL) and SOCl₂ (4.8 mL, 65.8 mmol, 1.3 equivalent) was added. The mixturewas refluxed for 3 h and then volatiles were removed under reducedpressure. The residue was co-evaporated three times with MeOH and driedin vacuo (15.23 g).

Methyl 3-trifluoroacetamido-4-iodobenzoate

The aniline derivative from above (14.53 g, 52 mmol) was dissolved inDCM (200 mL) and TFAA (15 mL, 104 mmol) was added. The dark purplesolution was refluxed overnight. Volatiles were removed under reducedpressure and the residue was passed through a short pad of silica gelusing DCM as eluent. The desired product was obtained as a pink solid(13.81 g).

4-Phenylethynyl-3-(2,2,2-trifluoro-ethanoylamino)-benzoic acid methylester

The iodide from above (0.742 g, 2 mmol), phenylacetylene (0.37 mL, 3.9mmol, 1.7 equivalent) and Et₃N (6 mL) were charged in a dry flask underargon. PdCl₂(PPh₃)₂ (0.241 g, 0.3 mmol) was added and the mixture wasstirred at room temperature until judged complete by HPLC analysis (˜5h). The reaction mixture was concentrated to half volume under reducedpressure and diluted with water (80 mL). The mixture was extracted withEtOAc (3×100 mL) and the organic extract washed with 5% HCl (100 mL),after (100 mL) and brine (40 mL). After drying over MgSO₄, the residuewas purified by flash chromatography using 20% EtOAc-hexane as eluent togive the desired cross-coupled alkyne as a tan solid (0.442 g).

Methyl 3-(cyclohexenyl)-2-phenylindole 6-carboxylate

A flame-dried flask was charged with finely powdered anhydrous K₂CO₃(0.153 g, 1.1 mmol) and the alkyne derivative from above (0.390 g, 1.1mmol). Dry DMF (4 mL) was added and the suspension degassed with astream of argon. The enol triflate derived from cyclohexanone, preparedfollowing the procedure described by A. G. Martinez, M. Hanack et al.(J. Heterocyclic Chem. 1988, 25, 1237 or equivalent methods described inthe literature, (0.802 g, 3.3 mmol, 3 equivalents) was added followed byPd(PPh₃)₄ (0.086 g, 0.07 mmol) and the mixture was stirred for 8 h atroom temperature. DMF was removed under vacuum and the residue purifiedby flash chromatography using DCM as eluent (0.260 g).

Methyl 3-cyclohexyl-2-phenylindole-6-carboxylate

The material from above was hydrogenated (1 atm H₂ gas) over 20% Pd(OH)₂in the usual manner, using MeOH as solvent. The desired cyclohexaneindole was isolated after filtration of the catalyst.

3-Cylohexyl-2-phenylindole-6-carboxylic acid

The methyl ester from above (0.154 g, 0.15 mmol) was refluxed overnightin a mixture of MeOH (10 mL) and 2N NaOH (6 mL) until completehydrolysis had occurred as shown by HPLC analysis. After cooling to roomtemperature, 2N HCl (5 mL) was added followed by AcOH to pH 7. MeOH wasremoved under reduced pressure, water (50 mL) was added and the productextracted with EtOAc. The extract was washed with water an brine, anddried (MgSO₄). Removal of volatiles under reduced pressure gave thetitle indole carboxylic acid as a light-orange solid (0.149 g).

Following the same procedure but using 2-ethynylpyridine instead ofphenylacetylene, 3-cyclohexane-2-(2-pyridyl)indole-6-carboxylic acid wasobtained.

Example 2

3-Cyclohexenyl-6-indole carboxylic acid

A 12 L round-bottomed flask was equipped with a reflux condenser and amechanical stirrer, and the system was purged with nitrogen gas.6-Indole carboxylic acid (300.00 g, 1.86 mole, 3 equivalents) wascharged into the flask, followed by MeOH (5.5 L). After stirring for 10min at room temperature, cyclohexanone (579 mL, 5.58 mole) was added.Methanolic sodium methoxide (25% w/w, 2.6 L, 11.37 mole, 6.1equivalents) was added in portions over 10 min. The mixture was thenrefluxed for 48 h. After cooling to room temperature, water (4 L) wasadded and methanol removed under reduced pressure. The residual aqueousphase was acidified to pH 1 with concentrated HCl (˜1.2 L). Theresulting yellowish precipitate was collected by filtration, washed withwater and dried under vacuum at 50° C. The desired cyclohexanederivative was obtained as a beige solid (451.0 g, 100% yield).

3-Cyclohexyl-6-indole carboxylic acid

The unsaturated derivative from above was hydrogenated for 20 h under 55psi hydrogen gas pressure over 20% Pd(OH)₂/C (10.25 g) using 1:1THF-MeOH (2.5 L) as solvent. After filtration of the catalyst, volatileswere removed under reduced pressure and the residue was triturated withhexane. The beige solid was collected by filtration, washed with hexaneand dried under vacuum (356.4 g, 78% yield).

Methyl 3-cyclohexyl-6-indole carboxylate

A 5 L three-necked flask was equipped with a reflux condenser and amechanical stirrer, and the system was purged with nitrogen gas. Theindole carboxylic acid from above (300.00 g, 1.233 mole) was chargedinto the flask and suspended in MeOH (2 L). Thionyl chloride (5 mL,0.0685 mole, 0.05 equivalent) was added dropwise and the mixture wasrefluxed for 48 h. Volatiles were removed under reduced pressure and theresidue was triturated with hexane to give a beige solid that was washedwith hexane and dried under vacuum (279.6 g, 88% yield).

Methyl-2-bromo-3-cyclohexyl-6-indole carboxylate

Adapting the procedure of L. Chu (Tet. Lett. 1997, 38, 3871) methyl3-cyclohexyl-6-indole carboxylate (4.65 g, 18.07 mmol) was dissolved ina mixture of THF (80 mL) and CHCl₃ (80 mL). The solution was cooled inan ice bath and pyridinium bromide perbromide (pyridine tribromide, 7.22g, 22.6 mmol, 1.25 equivalent) was added. After stirring for 1.5 h at 0°C., the reaction was judged complete by TLC. It was diluted with CHCl₃(200 mL), washed with 1M NaHSO₃ (2×50 mL), saturated aqueous NaHCO₃(2×50 mL) and brine (50 mL). After drying over Na₂SO₄, the solvent wasremoved under reduced pressure and the residue crystallized fromTBME-hexane. The desired 2-bromoindole derivative was collected byfiltration, washed with hexane and dried (3.45 g). Evaporation of motherliquors gave a red solid that was purified by flash chromatography using15% EtOAc in hexane yielding an additional 3.62 g of pure material.Total yield was 5.17 g (85% yield).

Example 3 General Procedure for the Suzuki Cross-Coupling of Aryl andHeteroarylboronic Acids with 2-bromoindole Derivatives

Cross-coupling of aromatic/heteroaromatic boronic acid or esterderivatives with 2-bromoindoles such as the one described in example 2can be performed using any variations of the standard metal-catalyzedSuzuki cross-coupling reaction as described in the literature and wellknown to those skilled in the art. The following example serves toillustrate such a process and is non-limiting.

3-Cyclohexyl-2-furan-3-yl-1H-indole-6-carboxylic acid methyl ester

The 2-bromoindole of example 2 (8.92 g, 26.5 mmol), 3-furanboronic acid(B. P. Roques et al. J. Heterocycl. Chem. 1975, 12, 195; 4.45 g, 39.79mmol, 1.5 equivalent) and LiCl (2.25 g, 53 mmol, 2 equivalents) weredissolved in a mixture of EtOH (100 mL) and toluene (100 mL). A 1Maqueous Na₂CO₃ solution (66 mL, 66 mmol) was added and the mixture wasdegassed with argon for 45 min. Pd(PPh₃)₄ (3.06 g, 2.65 mmol, 0.1equivalent) was added and the mixture stirred overnight at 75-85° C.under argon. Volatiles were removed under reduced pressure and theresidue re-dissolved in EtOAc (500 mL). The solution was washed withwater, saturated NaHCO₃ (100 mL) and brine (100 mL). After drying over amixture of MgSO₄ and decolorizing charcoal, the mixture was filtered andconcentrated under reduced pressure. The residual oil was trituratedwith a mixture of TBME (20 mL) and hexane (40 mL), cooled in ice and theprecipitated solid collected by filtration, washed with cold 25% TBME inhexane, and dried (3.09 g). The filtrate and washings from the abovetrituration were combined, concentrated and purified by flashchromatography using 10-25% EtOAc in hexane to give an additional 4.36 gof product. The total yield of the 2-(3-furyl)indole of example 3 was8.25 g.

Example 4

Methyl 3-cyclohexyl-1-methyl-6-indole carboxylate

Methyl 3-cyclohexyl-6-indole carboxylate from example 2 (150.00 g, 0.583mole) was charged into a 3 L three-necked flask equipped with amechanical stirrer and purged with nitrogen gas. DMF (1 L) was added andthe solution was cooled in an ice-bath. NaH (60% oil dispersion, 30.35g, 0.759 mole, 1.3 equivalent) was added in small portions (15 min) andthe mixture was stirred for 1 h in the cold. Iodomethane (54.5 mL, 0.876mole, 1.5 equivalent) was added in small portions, maintaining aninternal temperature between 5-10° C. The reaction mixture was thenstirred overnight at room temperature. The reaction was quenched bypouring into ice-water (3 L), resulting in the formation of acream-colored precipitate. The material was collected by filtration,washed with water and dried in vacuum at 45° C. (137.3 g, 86% yield).

Methyl 2-bromo-3-cyclohexyl-1-methyl-6-indole carboxylate

The 1-methylindole derivative from above (136.40 g, 0.503 mole) wascharged into a 5 L three-necked flask equipped with a mechanical stirrerand purged with nitrogen gas. CHCl₃ (750 mL) and THF (750 mL) were addedand the solution was cooled to 0° C. Pyridine tribromide (pyridiniumbromide perbromide, 185.13 g, 0.579 mole, 1.15 equivalent) was added insmall portions and the mixture was stirred for 1 h at 0° C. The solventwas removed under reduced pressure at room temperature and the residuedissolved in EtOAc (3 L). The solution was washed with water and brine,dried (decolourising charcoal/MgSO₄) and concentrated under reducedpressure. The residue was suspended in TBME and heated to 50° C. Thesuspension was stored overnight in the refrigerator and thecream-coloured crystalline product was collected by filtration. It waswashed with TBME and dried in vacuum (134.3 g, 76% yield).

Example 5 Cyclohexyl-methyl-tributylstannanyl-1H-indole-6-carboxylicacid methyl ester

The bromoindole derivative of example 4 (2.70 g, 7.71 mmol) wasdissolved in dry THF (40 mL) and the solution was cooled to −78° C.under an argon atmosphere. A solution of nBuLi in hexane (1.4 M, 6.90mL, 9.64 mmol, 1.25 equivalent) was added dropwise over 15 min andstirring at low temperature was continued for 75 min. To the resultingsuspension was added nBu₃SnCl (2.93 mL, 10.8 mmol, 1.4 equivalent) over5 min. The suspension dissolved and the solution was stirred for 1 h at−78° C. The reaction mixture was warmed to room temperature and THFremoved under reduced pressure. The residue was dissolved in TBME (150mL), washed with 1:1 brine-water and dried over MgSO₄. The material waspurified by chromatography on silica gel that was previously deactivatedby mixing with a solution of 5% Et₃N in hexane. The same solvent wasused as eluent for the chromatography. The title stannane was isolatedas a yellow oil (3.42 g, 79% yield).

Example 6 General Procedure for Stille Cross-Coupling of the 2-StannaneIndole of Example 5 with Aromatic/Heteroaromatic Halides

Cross-coupling of aromatic/heteroaromatic halides or pseudohalides(preferably bromides, iodides and triflates) with the stannanederivative of example 5 can be performed using any variations of thestandard metal-catalyzed Stille cross-coupling reaction as described inthe literature. The following example serves to illustrate such aprocess.

3-Cyclohexyl-1-methyl-2-pyridin-2-yl-1H-indole-6-carboxylic acid methylester

The stannane derivative of example 5 (3.42 g, 6.1 mmol) was dissolved inDMF (10 mL) and CuI (0.116 g, 0.61 mmol, 0.1 equivalent), LiCl (0.517 g,12.21 mmol, 2 equivalent), triphenylphosphine (0.320 g, 1.22 mmol, 0.2equivalent) and 2-bromopyridine (0.757 mL, 7.94 mmol, 1.3 equivalent)were added. The solution was degassed with a stream of argon (30 min)and Pd(PPh₃)₄ (0.352 g, 0.31 mmol, 0.05 equivalent) was added. Afterpurging with argon for an additional 10 min, the solution was heated andstirred at 100° C. overnight under argon. The DMF was then removed undervacuum and the residue dissolved in EtOAc (150 mL). The solution waswashed with 1N NaOH (25 mL) and brine (25 mL) and dried over MgSO₄. Thesolvent was removed under reduced pressure and the residue purified byflash chromatography eluting with CHCl₃ then 5-10% EtOAc in CHCl₃ (1.516g, 71% yield).

Example 7 General Procedure for Stille Cross-Coupling of 2-bromoindoleswith Aryl or Heteroarylstannanes3-Cyclohexyl-1-methyl-2-pyridin-2-yl-1H-indole-6-carboxylic acid methylester

The 2-bromoindole derivative of example 4 (0.150 g, 0.428 mmol) and2-trimethylstannylthiophene (S. F. Thames et al. J. Organometal. Chem.1972, 38, 29; 0.150 g, 0.61 mmol, 1.4 equivalent) were dissolved in dryTHF (7 mL) in a sealed tube, and the solution was degassed with a streamor argon for 30 min. Pd(Cl)₂(PPh₃)₂ (0.018 g, 0.026 mmol, 0.06equivalent was added and the tube sealed. The solution was heated to 80°C. for 40 h. The reaction mixture was cooled to room temperature, EtOAc(10 mL) was added and the suspension filtered. After evaporation of thesolvent, the residue was re-submitted to the reaction conditions for anadditional 20 h, with fresh 2-stannylthiophene (0.150 g, 0.61 mmol) andcatalyst (0.020 g). After cooling to room temperature and filtration ofsolids, the solvent was evaporated and the residue purified by flashchromatography using 15-100% CHCl₃ in hexane as eluent (0.133 g, 88%yield).

The same procedure can be used to couple stannane derivatives to the2-bromoindole of Example 2.

Example 8 General Procedure for the N-alkylation of 2-aryl and2-heteroaryl-6-indole carboxylates3-Cyclohexyl-1-methyl-2-pyridin-2-yl-1H-indole-6-carboxylic acid methylester

NaH (60% oil dispersion, 0.186 g, 4.64 mmol, 1.5 equivalent) was washedwith hexane (20 mL) to remove the oil and then re-suspended in DMF (5mL). After cooling to 0° C. in an ice bath, the indole derivative ofexample 3 (1.000 g, 3.09 mmol) was added dropwise as a solution in DMF(3 mL+2 mL rinse). After stirring for 15 min, iodomethane (0.385 mL,6.18 mmol, 2 equivalents) was added in one portion and the mixture wasstirred for 2 h in the cold and an additional 2 h at room temperature.The reaction was then quenched by addition of 1N HCl (1 mL) and dilutedwith TBME (100 mL). The solution was washed with 1N HCl (25 mL) anddried (MgSO₄). After removal of volatiles under reduced pressure, theresidue was purified by flash chromatography using 5-10% EtOAc in hexaneas eluent to give the title compound as a white solid (0.903 g, 86%yield).

Other N-alkylindole derivatives within the scope of this invention couldbe prepared from the appropriate electrophiles (e.g. Etl, iPrl, iBul,BnBr) using a similar procedure.

Example 9 General Procedure for the Saponification of6-indolecarboxylates to the Corresponding Free Carboxylic Acids

This procedure applies to both indole and N-methylindole carboxylates.

3-Cyclohexyl-1-methyl-2-pyridin-2-yl-1H-indole-6-carboxylic acid

The 6-indole carboxylate of example 6 (1.517 g, 4.35 mmol) was dissolvedin DMSO (8 mL) and 5N NaOH (4.4 mL) was added. The mixture was stirredat 50° C. for 30 min. The solution was then cooled to room temperatureand added dropwise to water (15 mL). Insoluble black impurities wereremoved by filtration and AcOH (2 mL) was added dropwise to thefiltrate. The white precipitate that formed was collected by filtration,washed with water and dried (1.37 g, 94% yield).

Example 10 1-Cyclohexyl-2-phenyl-1H-indole-5-carboxylic acid

Ethyl 4-amino-3-iodobenzoate

Ethyl 4-aminobenzoate (15.00 g, 91 mmol) and iodine (11.80 g, 46.5 mmol)were mixed with water (80 mL) and chlorobenzene (4.60 g, 41 mmol). Themixture was stirred while the temperature was gradually raised to 90° C.over 30 min. Hydrogen peroxide (30%, 50 mL) was added over 10 h at 90°C. After stirring at that temperature for an additional 6 h, the mixturewas cooled and the solution decanted from the residual solids. Thesolids were dissolved in DCM and the solution washed successively withsodium thiosulfate and brine. After drying (MgSO₄), the solvent wasremoved under reduced pressure and the resulting brown solid wastriturated with hexane to remove di-iodinated by-products. The desiredcompound was obtained as a brown solid (22.85 g, 86% yield).

Ethyl 4-acetamido-3-iodobenzoate

The aniline from above (1.00 g, 3.44 mmol) was dissolved in pyridine (5mL) and the solution was cooled in ice. AcCl (0.32 mL, 4.47 mmol, 1.3equivalent) was added dropwise and the mixture was stirred for 1 h at 0°C. and 2 h at room temperature. The reaction mixture was then dilutedwith 1 N HCl and the product was extracted with TBME (100 mL). Theorganic phase was washed with 1N HCl (50 mL), dried (MgSO₄) andconcentrated to give the desired material as a tan-colored solid (1.121g, 97% yield).

Ethyl 2-phenyl-indole-5-carboxylate

Following the procedure of A. Bedeschi et al. (Tet. Lett. 1997, 38,2307), the acetanilide derivative from above (0.900 g, 2.7 mmol) wasreacted with phenylacetylene (0.385 mL, 3.5 mmol, 1.3 equivalent) in thepresence of PdCl₂(PPh₃)₂ (10 mole %) and CuI (10 mole %) in a mixture ofdioxane (5 mL) and tetramethylguanidine (5 mL). The desired2-phenylindole (0.589 g, 82% yield) was isolated as a yellow solid afterflash chromatography with 15% EtOAc in hexane.

1-Cyclohex-1-enyl-2-phenyl-1H-indole-5-carboxylic acid ethyl ester

The 2-phenylindole derivative from above (0.265 g, 1.0 mmol) wasdissolved in DMF (2 mL) and cesium hydroxide monohydrate (0.208 g, 1.2mmol, 1.2 equivalent) was added. The solution was cooled in an ice bathand 3-bromocyclohexene (0.193 g, 1.2 mmol, 1.2 equivalent) was addeddropwise (5 min) as a solution in DMF (1 mL). The mixture was stirredfor 30 min at 0° C. The reaction was diluted with water (25 mL),extracted with Et₂O (2×50 mL) and the extract dried over MgSO₄. Thesolvent was evaporated under reduced pressure to give a white foam(0.095 g) that was used without purification in the next step.

1-Cyclohexyl-2-phenyl-1H-indole-5-carboxylic acid

The crude indole from above was hydrogenated in the usual way (1 atm H₂gas) in EtOH over 20% Pd(OH)₂ on carbon for 20 h at room temperature.After filtration of the catalyst, the EtOH was removed under reducedpressure. The residue was dissolved in a mixture of MeOH (1 mL) and DMSO(1 mL) and 5N NaOH (0.5 mL) was added. The mixture was stirred overnightat 50° C. The reaction mixture was cooled and water (10 mL) was added.After acidification with 1N HCl, the product was extracted into Et₂O (70mL) and the solution dried (Na₂SO₄). Evaporation of the solvent gave agreen residue consisting of a 2:1 mixture (85 mg) of the desired1-cyclohexyl-2-phenylindole-5-carboxylic acid and1,3-dicyclohexyl-2-phenylindole-5-carboxylic acid.

Example 11 1-Cyclohexyl-3-methyl-2-phenyl-1H-indole-5-carboxylic acid

Ethyl 2-phenyl-3-methyl-indole-5-carboxylate

Adapting the procedure of H.-C. Zhang (Tet. Lett. 1997, 38, 2439) ethyl4-amino-3-iodobenzoate (from example 10, 0.500 g, 1.72 mmol) wasdissolved in DMF (5 mL) and LiCl (0.073 g, 1.72 mmol, 1 equivalent),PPh₃ (0.090 g, 0.34 mmol, 0.2 equivalent), K₂CO₃ (1.188 g, 8.6 mmol, 5equivalents) and phenylpropyne (0.645 mL, 5.76 mmol, 3 equivalents) wereadded. The solution was degassed by purging with argon for 1 h andpalladium acetate (0.039 g, 0.17 mmol, 0.1 equivalent) was added. Themixture was stirred at 80° C. under argon for 20 h. The reaction mixturewas diluted with water (25 mL) and extracted with EtOAc (50 mL). Theextract was washed with brine (3×25 mL) and dried (MgSO₄). Concentrationunder reduced pressure and purification by flash chromatography with10-15% EtOAc-hexane gave the desired 2-phenyl-3-methyl indole (0.275 g,least polar component) and the 3-phenyl-2-methyl isomer (0.109 g, morepolar component).

Ethyl 1-(3-cyclohexenyl)-3-methyl-2-phenylindole-5-carboxylate

The less polar isomer from above (0.264 g, 0.95 mmol) was dissolved inDMSO (2 mL) and cesium hydroxide monohydrate (0.191 g, 1.14 mmol, 1.2equivalent) was added followed by 3-bromocyclohexene (0.183 g, 1.14mmol, 1.2 equivalent in 0.7 mL of DMSO). The mixture was stirred at roomtemperature for 30 min. Additional CsOH monohydrate (0.400 g, 2.4equivalents) and 3-bromocyclohexene (0.400 g, 2.4 equivalents) wereadded and stirring continued for an additional 30 min. Similar amountsof the two reagents were again added and after another 30 min ofstirring at room temperature, the reaction was diluted with 1N HCl (6mL) and water (20 mL). The product was extracted with TBME (100 mL),dried (MgSO₄) and after concentration under reduced pressure, theresidue was purified by flash chromatography using 5-10% EtOAc in hexaneas eluent. The desired N-alkylated indole was obtained (0.130 g).

Ethyl 1-cyclohexyl-3-methyl-2-phenylindole-5-carboxylate

The unsaturated product from above was hydrogenated (1 atm H₂ gas) inthe usual way over 20% Pd(OH)₂ in EtOH at room temperature for 3 h.

1-Cyclohexyl-3-methyl-2-phenyl-1H-indole-5-carboxylic acid

The hydrogenated material from above was dissolved in a mixture of DMSO(2 mL) and MeOH (2 mL). 5N NaOH (0.5 mL) was added and the mixture wasstirred overnight at 60° C. After dilution with water (40 mL), theproduct aqueous phase was washed with a 1:1 mixture of Et₂O-hexane (50mL) and then acidified with 1N HCl to pH 1. The liberated free acid wasextracted with diethyl ether (2×50 mL) and the extract dried overNa₂SO₄. Removal of the solvent under reduced pressure gave the desiredindole as a light brown solid (0.074 g).

Example 12 2-Bromo-3-cyclopentyl-1-methyl-1H-indole-6-carboxylic acidmethyl ester

A 3 L three-necked flask equipped with a mechanical stirrer was chargedwith indole 6-carboxylic acid (220 g, 1.365 mole) and KOH pellets(764.45 g, 13.65 mole, 10 equivalents). Water (660 mL) and MeOH (660 mL)were added and the mixture heated to 75° C. Cyclopentanone (603.7 mL,6.825 mole, 5 equivalents) was added dropwise over 18 h using a pump.The reaction mixture was heated for an additional 3 h (after which thereaction was judged complete by HPLC) and cooled to 0° C. for 1 h. Theprecipitated potassium salt is collected by filtration, and washed withTBME (2×500 mL) to remove cyclopentanone self-condensation products. Thebrown solid was re-dissolved in water (2.5 L) and the solution washedwith TBME (2×1 L). Following acidification to pH 3 with conc. HCl (425mL), the beige precipitate was collected by filtration, washed withwater (2×1 L) and dried under vacuum at 70° C. The crude product weighed275.9 g (88.9% mass recovery) and had an homogeneity of 85% (HPLC).

The crude product from above (159.56 g, 0.70 mole) was dissolved in MeOH(750 mL) and 20% Pd(OH)₂ on charcoal (8.00 g) was added. The mixture washydrogenated in a Parr apparatus under 50 psi hydrogen gas for 18 h.After completion, the catalyst was removed by filtration through celiteand the solvent removed under reduced pressure. The resulting brownsolid was dried at 70° C. under vacuum for 12 h. The crude product(153.2 g) was obtained as a brown solid and was 77% homogeneous by HPLC.

The crude 3-cyclopentylindole-6-carboxylic acid (74.00 g, 0.323 mole)was charged in a 3 L three-necked flask equipped with a mechanicalstirrer and a thermometer. The system was purged with nitrogen gas andanhydrous DMF (740 mL) was added. After dissolution on the startingmaterial, anhydrous potassium carbonate (66.91 g, 0.484 mole, 1.5equivalent) was added and the mixture stirred for 5 minutes. Iodomethane(50 mL, 0.807 mole, 2.5 equivalents) was added and the mixture stirredfor 5 h after which HPLC analysis of the reaction mixture indicated 97%conversion to the methyl ester.

The reaction mixture was cooled in an ice bath and sodium hydride (95%,oil-free, 10.10 g, 0.420 mole, 1.3 equivalent) was added in smallportions over 3 min (exothermic: 8° C. to 30° C. internal temperatureraise). After stirring for an additional 15 min, the cooling bath wasremoved and stirring continued for 1.5 h at room temperature after whichno further progression was observed (HPLC). Additional NaH (1.55 g, 65mmol, 0.2 equivalent) and iodomethane (1.0 mL, 16 mmol, 0.05 equivalent)were added and after stirring for 15 min, the reaction was judgedcomplete by HPLC (96% N-methylated).

The reaction mixture was slowly (2 min) poured into water (4 L) withvigorous stirring and after 10 min, acidified to pH<2 with conc. HCl (85mL). The mixture was stirred for 5 min to allow complete conversion ofany remaining potassium carbonate and bicarbonate to the more solublechloride. The pH was adjusted to ˜7 with 4N NaOH (40 mL) and the mixturestirred overnight at room temperature. The precipitated material wascollected by filtration, washed with water (600 mL) and dried at 60° C.under vacuum. The crude product (79% homogeneity by HPLC) was obtainedas a brown solid (72.9 g).

The crude material from above is triturated with a minimal amount ofMeOH to remove a series of minor impurities. The solid was thencollected by filtration and dissolved in a minimal amount of hot EtOAc.After cooling to room temperature, hexane was added (5× volume) and themixture cooled in ice and filtered. The filtrate was then evaporated todryness to give the desired product.

The N-methylindole from above (10.60 g, 41.2 mmol) was dissolved inisopropyl acetate (150 mL) and sodium acetate (5.07 g, 62 mmol, 1.5equivalent) was added. The suspension was cooled in an ice bath andbromine (2.217 mL, 43.3 mmol, 1.05 equivalent) was added dropwise over 2min. The pale amber suspension turned dark red (exotherm from 5° C. to13° C.). It was stirred for 1 h at 0° C. The reaction was completed byadding additional bromine (0.21 mL, 4.2 mmol, 0.10 equivalent) as shownby HPLC analysis. The reaction was then quenched by addition of 10%aqueous sodium sulfite solution (15 mL), followed by water (50 mL) andK₂CO₃ (10.6 g, 1.8 equivalent) to neutralize HBr. The organic layer wasseparated, washed with 10% aqueous sodium sulfite and aqueous K₂CO₃ anddried (MgSO₄). The solvent was removed under reduced pressure and theresidue co-evaporated with TBME (75 mL) to give a beige solid that wasdried under vacuum overnight (13.80 g). The crude material wastriturated with boiling MeOH (80 mL) for 30 min, cooled in ice and thebeige solid collected by filtration. The product was dried at 60° C.under vacuum (10.53 g, 76% recovery).

Example 13 3-Cyclopentyl-1-methyl-2-vinyl-1H-indole-6-carboxylic acid

To the 2-bromoindole derivative of example 12 (2.044 g, 6.08 mmol) indry dioxane (20 mL) was added vinyltributyltin (1.954 mL, 6.69 mmol).The solution was degassed by bubbling nitrogen for 15 min. Thenbis(triphenylphosphine) palladium (II) chloride (213.4 mg, 0.304 mmol)was added and the reaction mixture was heated at 100° C. overnight. Thereaction mixture was diluted with ether and successively washed withwater and brine. After the usual treatment (MgSO₄, filtration andconcentration) the residue was flash chromatographed (5 cm, 10%AcOEt-hexane) to afford the desired compound (1.32 g, 4.70 mmol, 77%yield) as a white solid.

To the ester from above (153 mg, 0.54 mmol) in a mixture of THF (2.8 mL)and methanol (1.4 mL) was added an aqueous solution of lithium hydroxide(226.6 mg, 5.40 mmol in 1.6 mL of water). The reaction mixture wasstirred at 50° C. for 1.5 h and diluted with water. The aqueous layerwas acidified with 1M aq. HCl and extracted three times with CH₂Cl₂. Thecombined organic layers were successively washed with water (2×) andbrine. After the usual treatment (MgSO₄, filtration and concentration)the desired crude acid was isolated (150 mg).

Example 14 3-Cyclohexyl-1-methyl-2-oxazol-5-yl-1H-indole-6-carboxylicacid

To the bromide of example 4 (1.00 g, 2.855 mmol) in dry dioxane (10 mL)was added vinyltributyltin (917.8 μL, 3.141 mmol). The solution wasdegassed by bubbling nitrogen through for 15 min. Thenbis(triphenylphosphine) palladium (II) chloride (101 mg, 0.144 mmol) wasadded and the solution was refluxed for 7 hrs. The reaction mixture wasdiluted with ether and successively washed with water and brine. Afterthe usual treatment (MgSO₄, filtration and concentration) the residuewas flash chromatographed (5 cm, hexane to 2.5% AcOEt to 5% AcOEt to 10%AcOEt-hexane) to afford the desired compound (773 mg, 2.60 mmol, 91%yield) as a pale yellow solid.

To the olefinic derivative from above (100 mg, 0.336 mmol) in a mixtureof acetone (690 μL), tert-butanol (690 μL) and water (690 μL) weresuccessively added N-methylmorpholine N-oxide (NMMO; 48 mg, 0.410 mmol)and a 2.5% solution of osmium tetroxide in tert-butanol (33 μL). Thereaction mixture was stirred at room temperature for three days and thenconcentrated. The residue was dissolved in EtOAc and successively washedwith water (2×) and brine. After the usual treatment (MgSO₄, filtrationand concentration) the crude diol (117 mg) was isolated.

To the crude diol obtained above (ca. 0.336 mmol) in a mixture of THF(3.2 mL) and water (3.2 mL) at 0° C. was added sodium periodate (86.2mg, 0.403 mmol). The cooling bath was then removed and the reactionmixture was stirred at room temperature for 1 h 45 min. AcOEt was thenadded. The resulting solution was successively washed with 10% aq.citric acid, water, satd aq. NaHCO₃, water (2×) and brine. After theusual treatment (MgSO₄, filtration and concentration) the crude desiredaldehyde was isolated (92 mg, 0.307 mmol, 91% yield).

A mixture of the aldehyde from above (25.8 mg, 0.086 mmol), anhydrouspotassium carbonate (12.4 mg, 0.090 mmol) and Tosmic (17.57 mg, 0.090mmol) in absolute MeOH (500 μL) was refluxed for 2 h. AcOEt was thenadded and the mixture was successively washed with water (2×) and brine.After the usual treatment (MgSO₄, filtration and concentration) thecrude desired oxazole was isolated (28 mg, 0.083 mmol, 96% yield).

To the ester from above (28 mg, 0.083 mmol) in a mixture of THF (425μL), MeOH (210 μL) and water (250 μL) was added lithium hydroxide (34.8mg, 0.830 mmol). The reaction mixture was stirred overnight at roomtemperature, then diluted with water and acidified with a 1N aq. HClsolution. The aqueous layer was extracted with dichloromethane (3×) andsuccessively washed with water (2×) and brine. After the usual treatment(MgSO₄, filtration and concentration) the title crude acid was isolated(30 mg).

Example 152-(1H-Benzimidazol-2-yl)-3-cyclohexyl-1-methyl-1H-indole-6-carboxylicacid

To a mixture of the aldehyde from example 14 (28 mg, 0.094 mmol) and1,2-diaminobenzene (10.9 mg, 0.101 mmol) in acetonitrile (500 μL) andDMF (200 μL) was added chloranil (24.8 mg, 0.101 mmol). The reactionmixture was stirred at room temperature for three days. AcOEt was addedand the reaction mixture was successively washed with a 1N aq. NaOHsolution (2×), water (4×) and brine. After the usual treatment (MgSO₄,filtration and concentration) the residue was flash chromatographed (1cm, 30% AcOEt-hexane) to afford the desired benzimidazole esterderivative (11 mg, 0.028 mmol, 30% yield).

To the ester from above (11 mg, 0.028 mmol) in a mixture of THF (240μL), MeOH (120 μL) and water (140 μL) was added lithium hydroxide (11.7mg, 0.280 mmol). The reaction mixture was stirred overnight at roomtemperature, then diluted with water and acidified with a 1N aq. HClsolution. The aqueous layer was extracted with dichloromethane (3×) andsuccessively washed with water (2×) and brine. After the usual treatment(MgSO₄, filtration and concentration) the title crude acid was isolated(9 mg, 0.0241 mmol, 86% yield).

Example 16 3-Cyclopentyl-1-methyl-1H-indole-2,6-dicarboxylic acid6-methyl ester

To the 3-cyclopentyl aldehyde prepared in a similar fashion to thatdescribed in example 15 (20 mg. 0.07 mmol) and 2-methyl-2-butene (541μL, 5.11 mmol) in tert-butanol (500 μL) at 0° C. was added a freshlyprepared solution of sodium chlorite (64.2 mg, 0.711 mmol) in phosphatebuffer (98 mg of NaH₂PO₄ in 150 μL of water). The reaction mixture wasstirred for 45 min. at room temperature then brine was added. Theaqueous layer was extracted twice with EtOAc. The combined organic layerwas successively washed with a 0.5 N aq. HCl solution and brine. Afterthe usual treatment (MgSO₄, filtration and concentration) 23.1 mg of thedesired crude acid were isolated as a yellow solid.

Example 18 3-Cyclopentyl-2-pyridin-2-yl-benzofuran-6-carboxylic acid

The 2-bromobenzofuran derivative of example 17 (0.850 g, 2.93 mmol),2-tri(n-butyl)stannylpyridine (1.362 g, 3.7 mmol), triphenylphosphine(0.760 g, 2.90 mmol), lithium chloride (0.250 g, 5.9 mmol) and CuI(0.057 g, 0.3 mmol) were dissolved in DMF (30 mL) and the mixture wasdegassed by bubbling argon for 30 min.Tetrakis(triphenylphosphine)palladium (0.208 g, 0.18 mmol) was added andthe mixture stirred at 100° C. under an argon atmosphere. After 19 h,the reaction was cooled to room temperature, poured into water (70 mL)and extracted with TBME. The organic phase was washed with water (2×)and brine, dried (MgSO₄) and concentrated to give a residue that waspurified by flash chromatography. The desired 2(2-pyridyl)benzofuranderivative (0.536 g, 63% yield) was obtained as a white solid.

The nitrile from above (0.200 g, 0.694 mmol) was suspended in a mixtureof conc. H₂SO₄ (5 mL), AcOH (4 mL) and water (2 mL). After refluxing for1.5 h, TLC showed complete hydrolysis. The mixture was cooled in ice andthe 10 N NaOH was added dropwise to pH 9. The aqueous layer was washedwith dichloromethane and then acidified to pH 6 with 5 N HCl. Theproduct was extracted with EtOAc, dried (MgSO₄) and solvents removedunder reduced pressure. The desired carboxylic acid was obtained as awhite solid.

Example 19 2-Bromo-3-cyclopentyl-benzo[b]thiophene-6-carboxylic acidethyl ester

To a solution of 3-bromo-6-cyclopentanecarbonylphenol of Example 17(5.194 g, 19.30 mmol) in DMF (58.0 mL) was added1,4-diazabicyclo[2.2.2]octane (4.33 g, 38.60 mmol) anddimethylthiocarbamyl chloride (4.77 g, 38.6 mmol) at room temperature.The mixture was stirred at room temperature for 3 hr. The mixture wasacidified with 1 N HCl to pH 3 and then extracted with EtOAc. Theorganic layers were combined and washed with brine and dried over MgSO₄.The crude mixture was purified through a plug of silica gel with 3%EtOAc/hexanes to provide 6.976 g (100%) of the desired thiocarbamate asa colorless oil.

The neat O-3-bromo-6-cyclopentanecarbonyl N,N-dimethylthiocarbamate fromabove (43.147 g, 121.1 mmol) was heated to internal temperature of180-190° C. for 5 hr. TLC (20% EtOAc/hexanes: R_(f) 0.6 (startingmaterial), 0.5 (product)) was used to monitor the reaction progress. Thecrude material was used for the next reaction without furtherpurification.

The crude S-3-bromo-6-cyclopentanecarbonyl N,N-dimethylthiocarbamatefrom above was dissolved in MeOH (600 mL), KOH (40.0 g, 714 mmol) wasadded and the mixture was heated to reflux for 1.5 h. The mixture wascooled to room temperature and the solvent was removed by rotaryevaporation. The residue was dissolved in water and acidified by 6 N HClto pH 3. It was extracted with EtOAc and the crude product was purifiedby a silica gel chromatography with 1-5% EtOAc/hexanes. 31.3 g (91%) ofthe desired thiophenol derivative was obtained as a yellow oil.

To a solution of the 3-bromo-6-cyclopentanecarbonylthiophenol from above(0.314 g, 1.105 mmol) in acetone (5.0 mL) was added K₂CO₃ (0.477 g, 3.45mmol) followed by addition of ethyl bromoacetate (0.221 g, 0.147 mL,1.33 mmol). The mixture was stirred overnight. The reaction mixture wasfiltered through filter paper and the filtrate was concentrated.Purification by silica gel with 5% EtOAc/hexanes provided 0.334 g (82%)of the product as a colorless oil. The crude ester from above wasdissolved in THF (12.0 mL), 1 N NaOH (5.0 mL) was added at roomtemperature. The mixture was stirred at room temperature for 2-3 hr. oruntil TLC indicated complete reaction. The solvent was removed by rotaryevaporation. Water was added and the mixture was acidified with 6 N HClto pH 3 and extracted with EtOAc, washed with brine and dried overMgSO₄. The solvent was removed under reduced pressure and the residuewas used without further purification.

To the crude acid from above was added acetic anhydride (16.0 mL), andthen NaOAc (0.573 g) and the mixture was heated to reflux overnight. Themixture was cooled to room temperature and poured into a mixture of iceand toluene. 6 N NaOH was added until pH to about 7, and extracted withEtOAc, washed with brine and dried over MgSO₄. The solvent was removedby rotary evaporation and the residue was purified by silica gel withhexanes to provide 0.795 g (80%) of 6-bromo-3-cyclopentyl benzothiopheneas a colorless oil.

A mixture of the 6-bromo-3-cyclopentylbenzothiophene from above (0.723g, 2.57 mmol), and copper cyanide (0.272 g, 3.04 mmol) in DMF (1.4 mL)was heated to reflux overnight. The mixture was cooled to roomtemperature and diluted with EtOAc. 2 N NH₄OH was added and the mixturewas stirred for 10 minutes and filtered through Celite. The aqueouslayer was extracted with EtOAc. The organic layers were combined andwashed with brine, dried over MgSO₄, and the solvent was removed underreduced pressure. The product was used without further purification.

3-cyclopentyl-6-cyanobenzothiophene (17.65 g, 77.65 mmol) was dissolvedin acetic acid (310 mL), bromine (49.64 g, 310.6 mmol) was added at roomtemperature. The mixture was stirred at room temperature overnight andHPLC was used to monitor the reaction progress. After the reaction wascomplete, toluene was added to the reaction mixture to remove aceticacid (3×100 mL). The crude product was dried under reduced pressure andused without further purification.

The crude cyano derivative from above was added to ethanol (150 mL,denatured) and conc. H₂SO₄ (45 mL) and the mixture heated to reflux for1-2 days. After completion (HPLC) the reaction mixture was cooled toroom temperature and poured into ice-water and extracted withdichloromethane (5×100 mL), the organic layers were combined and washedwith 5% NaHCO₃, and brine. The solvent was removed under reducedpressure and the residue was purified with silica gel by 1%EtOAc/hexanes. The collected fractions were concentrated and the residuewas slurried in methanol. The solid was filtered and washed withice-cold methanol to provide 15.9 g (58%, two steps) of pure ethyl esteras a slight yellow solid.

Example 20 3-Cyclopentyl-2-pyridin-2-yl-benzo[b]thiophene-6-carboxylicacid

The 2-bromobenzothiophene of example 19 (0.354 g, 1.00 mmol),2-tri(n-butyl)stannylpyridine (0.442 g, 1.2 mmol), triphenylphosphine(0.262 g, 1.00 mmol), lithium chloride (0.085 g, 2.0 mmol) and CuI(0.019 g, 0.1 mmol) were dissolved in DMF (10 mL) and the mixture wasdegassed by bubbling argon for 30 min.Tetrakis(triphenylphosphine)palladium (0.069 g, 0.06 mmol) was added andthe mixture stirred at 100° C. under an argon atmosphere. After 24 h,the reaction was cooled to room temperature, poured into water (70 mL)and extracted with TBME. The organic phase was washed with water (2×)and brine, dried (MgSO₄) and concentrated to give a residue that waspurified by flash chromatography. The desired 2(2-pyridyl)benzothiopheneester (0.197 g, 56% yield) was obtained as a pale yellow waxy solid.

The ester from above was hydrolyzed in the usual manner using NaOH, togive the title acid that could be used directly or purified by HPLC andflash chromatography.

The acid could be coupled to amine derivatives following the generalprocedure described in example 37.

Example 21 3-Cyclopentyl-2-furan-3-yl-benzo[b]thiophene-6-carboxylicacid

The 2-bromobenzothiophene ester of example 19 was coupled to3-furanboronic acid as described in example 3 to give the desired2(3-furyl)benzothiophene ester in 85% yield. Saponification of the ethylester was carried out with NaOH at room temperature to give the titlecarboxylic acid derivative.

Example 223-Cyclohexyl-1-methyl-2-phenyl-1H-pyrrolo[2,3,b]pyridine-6-carboxylicacid

7-Azaindole (15.00 g, 0.127 mole) was dissolved in MeOH (330 mL) andsodium methoxide (25% w/w in MeOH, 172 mL, 0.753 mole) and cyclohexanone(52.86 mL, 0.51 mole) were added. The mixture was refluxed for 60 h andthen concentrated under reduced pressure. After cooling in ice-water,the reaction mixture was acidified to pH 8 with 3N HCl and theprecipitated solid was collected by filtration. The product was washedwith water, triturated with TBME-hexane and dried by azeotroping withtoluene (19.8 g).

The material from above (15.00 g, 75.65 mmol) was dissolved in a mixtureof EtOH (130 mL) and THF (30 mL) and 20% Pd(OH)₂ on carbon (1.30 g) wasadded. The mixture was hydrogenated under 1 atm of H₂ gas for 24 h,after which point additional catalyst (1.30 g) was added. After stirringunder H₂ gas for an additional 16 h, the catalyst was removed byfiltration and the solution evaporated under reduced pressure to give aresidue that was triturated with TBME to give an amber solid (13.9 g).

The azaindole derivative from above (7.50 g, 37.45 mmol) was dissolvedin DME (130 mL) and meta-chloroperbenzoic acid (12.943 g, 60.0 mmol) wasadded. After stirring for 2 h, volatiles were removed under reducedpressure and the residue suspended in water (100 mL). The mixture wasbasified to pH 10 by addition of saturated aqueous Na₂CO₃ solution undervigorous stirring. The solid was then collected by filtration, washedwith water and a small amount of TBME, and dried (7.90 g).

The crude N-oxide from above (4.00 g, 18.49 mmol) was dissolved in DMF(350 mL) and NaH (60% dispersion, 1.52 g, 38 mmol) was added in smallportions over 5 min. The mixture was stirred for 30 min and iodomethane(1.183 mL, 19 mmol) was added dropwise over 20 min to the suspension.After stirring for 3 h at room temperature, no more progress wasmeasured by HPLC analysis. The reaction mixture was poured into waterand extracted 3 times with EtOAc. The extract was washed with brine,dried (MgSO₄) and evaporated to give an amber solid (3.65 g, 60%homogeneity by NMR) that was used immediately without purification.

The crude product from above (0.80 g, 3.47 mmol) was dissolved in MeCN(10 mL). Triethylamine (1.13 mL, 8.1 mmol) was added followed bytrimethylsilyl cyanide (2.13 mL, 16 mmol). The solution was thenrefluxed for 19 h. After cooling to room temperature, the reaction wasquenched by slow addition of aqueous NaHCO₃ and the product extractedwith EtOAc. The extract was washed with brine, dried (MgSO₄) andconcentrated to a residue that was purified by flash chromatography onsilica gel using 15% EtOAc-hexane (0.285 g). The nitrile (0.300 g, 1.254mmol) was suspended in EtOH (15 mL) and hydrogen chloride gas wasbubbled through for 15 min to give a clear solution. The solution wasthen refluxed for 1.5 h until TLC showed complete conversion of startingmaterial. After cooling to room temperature, volatiles were removedunder reduced pressure and the residue was dissolved in EtOAc. Thesolution was washed with brine, dried (MgSO₄) and concentrated. Theresidue was purified by flash chromatography on silica gel (15-20%EtOAc-hexane) to give the desired ethyl ester as a pale yellow gum(0.227 g).

The ester from above (0.100 g, 0.35 mmol) was dissolved in THF (4 mL)and pyridinium hydrobromide perbromide (0.200 g, 0.532 mmol) was added.The mixture was stirred at 65° C. in a sealed vial for 16 h (>80%conversion). The solution was evaporated and the residue taken up intoEtOAc. The solution was washed with water and brine, dried (MgSO₄) andconcentrated. The crude material was purified by flash chromatography onsilica gel (15% EtOAc-hexane). The bromide from above (0.100 g, 0.274mmol), phenylboronic acid (0.049 g, 0.4 mmol) and lithium chloride(0.019 g, 0.45 mmol) were dissolved in a mixture of toluene (2 mL), EtOH(2 mL) and 1M Na₂CO₃ (0.43 mL). The mixture was degassed by passingargon gas through the solution for 30 min, andtetrakistriphenylphosphine palladium (0.035 g, 0.03 mmol) was added. Themixture was refluxed for 18 h after which point more catalyst (0.035 g,0.03 mmol) was added. After refluxing for an additional 2 h, the EtOHwas removed under reduced pressure. The residue was dissolved in EtOAcand the solution washed with 10% aqueous HCl and brine, and dried(MgSO₄). Removal of volatiles under reduced pressure gave an orange gumthat was purified by flash chromatography on silica gel using 20%EtOAc-hexane (0.105 g, crude).

The partially purified ester from above (0.100 g, 0.276 mmol) wasdissolved in a mixture of THF (2 mL) and EtOH (2 mL). 1N NaOH (2.8 mL)was added and the mixture stirred for 4 h at room temperature. Volatileswere removed under reduced pressure and the residue diluted with 10%aqueous HCl. The product was extracted with EtOAc (3×), dried (MgSO₄),evaporated and purified by reversed-phase preparative HPLC to give thetitle compound.

Example 23 Inhibition of NS5B RNA Dependent RNA Polymerase Activity

The compounds of the invention were tested for inhibitory activityagainst the hepatitis C virus RNA dependant polymerase (NS5B), accordingto the following assay:

The substrates are:

a 12 nucleotide RNA oligo-uridylate (or oligo-uridine-monophosphate)(oligo-U) primer modified with biotin at the free 5° C. position;

a complementary poly-adenylate (or adenosine monophosphate) (polyA)template of heterogeneous length (1000-10000 nucleotides); and UTP-[5,6³H].

Polymerase activity is measured as the incorporation of UMP-[5,6 ³H]into the chain elongated from the oligo-U primer. The ³H-labelledreaction product is captured by SPA-beads coated with streptavidin andquantified on the TopCount.

All solutions were made from DEPC treated MilliQ water [2 ml of DEPC isadded to 1 L of MilliQ water; the mixture is shaken vigorously todissolve the DEPC, then autoclaved at 121° C. for 30 minutes].

Enzyme: The full length HCV NS5B (SEQ ID NO. 1) was purified as anN-terminal hexa-histidine fusion protein from baculovirus infectedinsect cells. The enzyme can be stored at −20° C. in storage buffer (seebelow). Under these conditions, it was found to maintain activity for atleast 6 months.

Substrates: The biotinylated oligo-U₁₂ primer, the Poly(A) template, andthe UTP-[5,6 ³H] were dissolved in water. The solutions can be stored at−80° C.

Assay buffer: 20 mM Tris-HCl pH 7.5 5 mM MgCl₂ 25 mM KCl 1 mM EDTA 1 mMDTT NS5B storage buffer: 0.1 μM NS5B 25 mM Tris-HCl pH 7.5 300 mM NaCl 5mM DTT 1 mM EDTA 0.1% n-Dodecyl maltoside 30% glycerol

Test compound cocktail: Just prior to assay, test compounds of theinvention were dissolved in assay buffer containing 15% DMSO.

Substrate cocktail: Just prior to assay, the substrates were mixed inassay buffer to the following concentrations:

Concentration in Final Concentration Component substrate cocktail inassay RNAsin ™ 0.5 U/μL 1.67 U/μL Biotin-oligo-U₁₂ 3 ng/μL 1 ng/μLprimer PolyA template 30 ng/μL 10 ng/μL UTP-[5,6-³H] 35 0.025 μCi/μL0.0083 μCi/μL Ci/mmol 0.25 μM UTP 2.25 μM 0.75 μM

Enzyme cocktail: Just prior to assay, the RNA polymerase (NS5B) cocktailwas prepared in assay buffer to the following specifications:

Component Concentration in cocktail Tris-HCl at pH 7.5 20 mM MgCl₂ 5 mMKCl 25 mM EDTA 1 mM DTT 1 mM n-Dodecyl maltoside 1% NS5B 30 nM

Protocol:

The assay reaction was performed in a Microfluor™ white “U” bottom plate(Dynatech™ #7105), by successively adding:

20 μL of test compound cocktail;

20 μL of substrate cocktail; and

20 μL of enzyme cocktail

(final [NS5B] in assay=10 nM; final [n-dodecyl maltoside] inassay=0.33%; final DMSO in assay=5%).

The reaction was incubated at room temperature for 1.5 hours. STOPsolution (20 μL; 0.5 M EDTA, 150 ng/μl tRNA) was added, followed by 30μl streptavidin coated PVT beads (8 mg/ml in 20 mM Tris-HCl, pH 7.5, 25mM KCl, 0.025% NaN₃). The plate was then shaken for 30 minutes. Asolution of CsCl was added (70 μL, 5 M), to bring the CsCl concentrationto 1.95 M. The mixture was then allowed to stand for 1 hour. The beadswere then counted on a Hewlett Packard TopCount™ instrument using thefollowing protocol:

Data mode: counts per minute

Scintillator: liq/plast

Energy range: low

Efficiency mode: normal

Region: 0-50

Count delay: 5 minutes

Count time: 1 minute

Expected results: 6000 cpm/well

200 cpm/well no enzyme control.

Based on the results at ten different concentrations of test compound,standard concentration-% inhibition curves were plotted and analysed todetermine IC₅₀'s for the compounds of the invention. For some compoundsthe IC₅₀ was estimated from two points.

Example 24 Specificity of NS5B RNA Dependent RNA Polymerase Inhibition

The compounds of the invention were tested for inhibitory activityagainst polio virus RNA dependent RNA polymerase and calf thymus DNAdependent RNA polymerase II in the format that is described for the HCVpolymerase with the exception that another polymerase was used in placeof the HCV NS5B polymerase.

Example 25 Cell Based HCV RNA Replication Assay

Cell Culture

Huh7 cells that stably maintain a subgenomic HCV replicon wereestablished as previously described (Lohman et al., 1999. Science 285:110-113) and designated as the S22.3 cell-line. S22.3 cells aremaintained in Dulbecco's Modified Earle Medium (DMEM) supplemented with10% FBS and 1 mg/mL neomycin (Standard Medium). During the assay, DMEMmedium supplemented with 10% FBS, containing 0.5% DMSO and lackingneomycin was used (Assay Medium). 16 hours prior to compound addition,S22.3 cells are trypsinized and diluted to 50 000 cells/ml in StandardMedium. 200 μL (10 000 cells) are distributed into each well of a96-well plate. The plate was then incubated at 37° C. with 5% CO₂ untilthe next day.

Reagents and Materials:

Product Company Catalog # Storage DMEM Wisent Inc. 10013CV 4° C. DMSOSigma D-2650 RT Dulbecco's PBS Gibco-BRL 14190-136 RT Fetal Bovine SerumBio-Whittaker 14-901F −20° C./4° C. Neomycin (G418) Gibco-BRL 10131-027−20° C./4° C. Trypsin-EDTA Gibco-BRL 25300-054 −20° C./4° C. 96-wellplates Costar 3997 RT PVDF 0.22 μm Millipore SLGV025LS RT Filter UnitDeep-Well Titer Beckman 267007 RT Plate PolypropylenePreparation of Test Compound

10 μL of test compound (in 100% DMSO) was added to 2 ml of Assay Mediumfor a final DMSO concentration of 0.5% and the solution was sonicatedfor 15 min and filtered through a 0.22 μM Millipore Filter Unit. 900 μlwas transferred into row A of a Polypropylene Deep-Well Titer Plate.Rows B to H, contain 400 μL aliquots of Assay Medium (containing 0.5%DMSO), and are used to prepare serial dilutions (½) by transferring 400μl from row to row (no compound was included in row H).

Application of Test Compound to Cells

Cell culture medium was aspirated from the 96-well plate containing theS22.3 cells. 175 μL of assay medium with the appropriate dilution oftest compound was transferred from each well of the compound plate tothe corresponding well of the cell culture plate (row H was used as the“No inhibition control”). The cell culture plate was incubated at 37° C.with 5% CO₂ for 72 hours.

Extraction of Total Cellular RNA

Following the 72 hour incubation period, the total cellular RNA wasextracted from the S22.3 cells of the 96-well plate using the RNeasy 96kit (Qiagen®, RNeasy Handbook. 1999.). Briefly, assay medium wascompletely removed from cells and 100 μL of RLT buffer (Qiagen®)containing 143 mM β-mercaptoethanol was added to each well of the96-well cell-culture plate. The microplate was gently shaken for 20 sec.100 μL of 70% ethanol was then added to each microplate well, and mixedby pipetting. The lysate was removed and applied to the wells of aRNeasy 96 (Qiagen®) plate that was placed on top of a Qiagen®Square-Well Block. The RNeasy 96 plate was sealed with tape and theSquare-Well Block with the RNeasy 96 plate was loaded into the holderand placed in a rotor bucket of a 4K15C centrifuge. The sample wascentrifuged at 6000 rpm (˜5600×g) for 4 min at room temperature. Thetape was removed from the plate and 0.8 ml of Buffer RW1 (Qiagen® RNeasy96 kit) was added to each well of the RNeasy 96 plate. The RNeasy 96plate was sealed with a new piece of tape and centrifuged at 6000 rpmfor 4 min at room temperature. The RNeasy 96 plate was placed on top ofanother clean Square-Well Block, the tape removed and 0.8 ml of BufferRPE (Qiagen® RNeasy 96 kit) was added to each well of the RNeasy 96plate. The RNeasy 96 plate was sealed with a new piece of tape andcentrifuged at 6000 rpm for 4 min at room temperature. The tape wasremoved and another 0.8 ml of Buffer RPE (Qiagen® RNeasy 96 kit) wasadded to each well of the RNeasy 96 plate. The RNeasy 96 plate wassealed with a new piece of tape and centrifuged at 6000 rpm for 10 minat room temperature. Tape was removed, the RNeasy 96 plate was placed ontop of a rack containing 1.2-mL collection microtubes. The RNA waseluted by adding 50 μL of RNase-free water to each well, sealing platewith a new piece of tape and incubated for 1 min at room temperature.The plate was then centrifuged at 6000 rpm for 4 min at roomtemperature. The elution step was repeated with a second volume of 50 μlRNase-free water. The microtubes with total cellular RNA are stored at−70° C.

Quantification of Total Cellular RNA

RNA was quantified on the STORM® system (Molecular Dynamics®) using theRiboGreen® RNA Quantification Kit (Molecular Probes®). Briefly, theRiboGreen reagent was diluted 200-fold in TE (10 mM Tris-HCl pH=7.5, 1mM EDTA). Generally, 50 μL of reagent was diluted in 10 mL TE. AStandard Curve of ribosomal RNA was diluted in TE to 2 μg/mL andpre-determined amounts (100, 50, 40, 20, 10, 5, 2 and 0 μL) of theribosomal RNA solution are then transferred in a new 96-well plate(COSTAR # 3997) and the volume was completed to 100 μL with TE.Generally, column 1 of the 96-well plate was used for the standard curveand the other wells are used for the RNA samples to be quantified. 10 μLof each RNA sample that was to be quantified, was transferred to thecorresponding well of the 96-well plate and 90 μL of TE was added. Onevolume (100 μL) of diluted RiboGreen reagent was added to each well ofthe 96-well plate and incubated for 2 to 5 minutes at room temperature,protected from light (a 10 μL RNA sample in a 200 μL final volumegenerates a 20× dilution). The fluorescence intensity of each well wasmeasured on the STORM® system (Molecular Dynamics®). A standard curvewas created on the basis of the known quantities of the ribosomal RNAand the resulting fluorescent intensities. The RNA concentration in theexperimental samples was determined from the standard curve andcorrected for the 20× dilution.

Reagents and Materials:

Product Company Catalog # Storage DEPC Sigma D5758  4° C. EDTA SigmaE5134 RT Trizma-Base Sigma T8524 RT Trizma-HCl Sigma T7149 RT CollectionTube Strips Qiagen 19562 RT Ribogreen RNA Molecular R11490 −20° C.Quantitation Kit Probe Rneasy 96 Kit Qiagen 74183 RT Square-Well BlocksQiagen 19573 RTReal-Time RT-PCR

The Real-Time RT-PCR was performed on the ABI Prism 7700 SequenceDetection System using the TaqMan EZ RT-PCR Kit from (Perkin-ElmerApplied Biosystems®). RT-PCR was optimized for the quantification of the5′ IRES of HCV RNA by using the Taqman technology (Roche MolecularDiagnostics Systems) similar to the technique previously described(Martell et al., 1999. J. Clin. Microbiol. 37: 327-332). The systemexploits the 5′-3′ nucleolytic activity of AmpliTaq DNA polymerase.Briefly, the method utilizes a dual-labeled fluorogenic hybridizationprobe (PUTR Probe) that specifically anneals to the template between thePCR primers (primers 8125 and 7028). The 5′ end of the probe contains afluorescent reporter (6-carboxyfluorescein [FAM]) and the 3′ endcontains a fluorescent quencher (6-carboxytetramethylrhodamine [TAMRA]).The FAM reporter's emission spectrum was suppressed by the quencher onthe intact hybridization probe. Nuclease degradation of thehybridization probe releases the reporter, resulting in an increase influorescence emission. The ABI Prism 7700 sequence detector measures theincrease in fluorescence emission continuously during the PCRamplification such that the amplified product was directly proportion tothe signal. The amplification plot was analysed early in the reaction ata point that represents the logarithmic phase of product accumulation. Apoint representing a defined detection threshold of the increase in thefluorescent signal associated with the exponential growth of the PCRproduct for the sequence detector was defined as the cycle threshold(C_(T)). C_(T) values are inversely proportional to the quantity ofinput HCV RNA; such that under identical PCR conditions, the larger thestarting concentration of HCV RNA, the lower the C_(T). A standard curvewas created automatically by the ABI Prism 7700 detection system byplotting the C_(T) against each standard dilution of known HCV RNAconcentration.

Reference samples for the standard curve are included on each RT-PCRplate. HCV Replicon RNA was synthesized (by T7 transcription) in vitro,purified and quantified by OD₂₆₀. Considering that 1 μg of thisRNA=2.15×10¹¹ RNA copies, dilutions are made in order to have 10⁸, 10⁷,10⁶, 10⁵, 10⁴, 10³ or 10² genomic RNA copies/5 μL. Total cellular Huh-7RNA was also incorporated with each dilution (50 ng/5 μL). 5 μL of eachreference standard (HCV Replicon+Huh-7 RNA) was combined with 45 μL ofReagent Mix, and used in the Real-Time RT-PCR reaction.

The Real-Time RT-PCR reaction was set-up for the experimental samplesthat were purified on RNeasy 96-well plates by combining 5 μl of eachtotal cellular RNA sample with 45 μL of Reagent Mix.

Reagents and Materials:

Product Company Catalog # Storage TaqMan EZ RT-PCR Kit PE AppliedN808-0236 −20° C. Biosystems MicroAmp Optical Caps PE Applied N801-0935RT Biosystems MicroAmp Optical 96- PE Applied N801-0560 RT Well ReactionPlate BiosystemsReagent Mix Preparation:

Volume for One Plate Volume for (μL) (91 one sample samples + FinalComponent (μL) Dead Volume) conc. Rnase-free water 16.5 1617 5× TaqManEZ buffer 10 980 1× Mn(OAc)₂ (25 mM) 6 588 3 mM dATP (10 mM) 1.5 147 300μM dCTP (10 mM) 1.5 147 300 μM dGTP (10 mM) 1.5 147 300 μM dUTP (20 mM)1.5 147 600 μM Forward Primer (10 μM) 1 98 200 nM Reverse Primer (10 μM)1 98 200 nM PUTR probe (5 μM) 2 196 200 nM rTth DNA polymerase 2 196 0.1U/μL (2.5 U/μL) AmpErase UNG (1 U/μL) 0.5 49 0.01 U/μL Total Volume 454410

Forward Primer Sequence (SEQ ID. 2): 5′-ACG CAG AAA GCG TCT AGC CAT GGCGTT AGT-3′ Reverse Primer Sequence (SEQ ID NO. 3): 5′-TCC CGG GGC ACTCGC AAG CAC CCT ATC AGG-3′ Note: Those primers amplify a region of256-nt present within the 5′ untranslated region of HCV.

PUTR Probe Sequence (SEQ ID NO. 4):

No Template Controls (NTC): On each plate, 4 wells are used as “NTC”.For these controls, 5 μl of water are added to the well in place of RNA.

Thermal Cycling Conditions:

50° C. 2 min 60° C. 30 min 95° C. 5 min 95° C. 15 sec {close oversizebrace} for 2 cycles 60° C. 1 min 90° C. 15 sec {close oversize brace}for 40 cycles 60° C. 1 min

Following the termination of the RT-PCR reaction the data analysisrequires setting of threshold fluorescence signal for the PCR plate anda standard curve was constructed by plotting the Ct value versus RNAcopy number used in each reference reaction. The Ct values obtained forthe assay samples are used to interpolate an RNA copy number based onthe standard curve.

Finally, the RNA copy number was normalized (based on the RiboGreen RNAquantification of the total RNA extracted from the cell culture well)and expressed as genome equivalents/μg of total RNA [ge/μg].

The RNA copy number [g.e./μg] from each well of the cell culture platewas a measure of the amount of replicating HCV RNA in the presence ofvarious concentrations of inhibitor. The % inhibition was calculatedwith the following equation:100−[(g.e./μg inh)/(g.e./μg ctl)×100].

A non-linear curve fit with the Hill model was applied to theinhibition-concentration data, and the 50% effective concentration(EC₅₀) was calculated by the use of SAS software (Statistical SoftwareSystem; SAS Institute, Inc. Cary, N.C.).

In Table 1 below, the following ranges apply:

IC₅₀: A=≧1 μM; B=1 μM-500 nM; and C<500 nM.

Ec₅₀: A=≧1 μM; and B=<1 μM

TABLE 1

Cpd. m/z # A R² R³ Z IC₅₀ EC₅₀ (M + H)⁺ 101 N—Me phenyl cyclohexyl OH A— 334.1 102 NH

cyclohexyl OH A A 310.0 103 NH

cyclohexyl OH A — 308.0 104 NH

cyclohexyl OH A — 324.0 (M − H) 105 NH Br cyclohexyl OH A — 319.9 106N—Me

cyclohexyl OH B A 335.2 107 N—Me

cyclohexyl OH B A 324.1 108 N—Me

cyclohexyl OH B B 349.1 109 N—Me

cyclohexyl OH C A 336.1 110 NH

cyclopentyl OH C — 296.0 111 N—Me

cyclopentyl OH C A 310.0 112 N—Me

cyclohexyl OH C A 350.1 113 N—Me

cyclopentyl OH C — 336.1 114

cyclohexyl OMe A A 382   115 N—Me

cyclopentyl OH B A 321   116

cyclohexyl OH C — 368.1 117 N—Me

cyclopentyl OH C A 327.1 118 N—Me

cyclopentyl OH C A 384.1 119 N—Me

cyclopentyl OH B A 356.2 120 N—Me

cyclopentyl OH A — 370.2 121 N—Me

cyclopentyl OH B A 341.1 122 N—Me

cyclopentyl OH A — 384.2 123 N—Me

cyclopentyl OH C A 400.2 124 N—Me

cyclopentyl OH A — 384.1 125 N—Me

cyclopentyl OH A — 440.2 126 N—Me

cyclopentyl OH A — 426.2 127 N—Me

cyclopentyl OH C A 413.2 128 N—Me

cyclopentyl OH C A 311.1 129 N—Me

cyclopentyl OH B A 327.1 130 N—Me

cyclopentyl OH A — 335.2 131 N—Me

cyclopentyl OH B A 335.2 132 N—Me

cyclopentyl OH C A 326.1 133 N—Me

cyclopentyl OH B A 335.2 134 N—Me

cyclopentyl OH B — 335.2 135 N—Me

cyclopentyl OH C A 322.2 136 N—Me

cyclopentyl OH B — 399.1 137 N—Me

cyclopentyl OH B — 366.1 138 S

cyclopentyl OH A A 324.1 139 N—Me

cyclohexyl OH C — 356.1 140 S

cyclopentyl OH A — 331.1 141 O

cyclopentyl OH A A 308.2 142 NH

cyclohexyl OH A — 321.1 143

cyclohexyl OH B — 379.2 144 N—Me

cyclopentyl OH A — 355.0 145 NH

cyclopentyl OH A A 307.1 146

cyclohexyl OH A — 471.1 147 N—Me

cyclopentyl OH A — 351.1 148 N—Me

cyclopentyl OH B — 339.1 149

cyclohexyl OH B — 457.2 150 N—Me

OH — — 319.0

TABLE 2

Cpd. m/z # A R² R³ Z IC₅₀ EC₅₀ (M + H)⁺ 201 N—Me phenyl cyclo- OH A —335.3 hexyl 202 N—Me

cyclo hexyl OH A — 325.2

1. A compound represented by Formula II

wherein: A is NR¹, wherein R¹ is H or (C₁₋₆)alkyl optionally substitutedwith: halogen, OR¹¹, SR¹¹ or N(R¹²)₂, wherein R¹¹ and each R¹² isindependently H, (C₁₋₆)alkyl, (C₃₋₇)cycloalkyl,(C₁₋₆)alkyl-(C₃₋₇)cycloalkyl, (C₁₋₆)alkyl-aryl or (C₁₋₆)alkyl-Het, saidaryl or Het optionally substituted with R¹⁰; or both R¹² are covalentlybonded together and to the nitrogen to which they are both attached toform a 5, 6 or 7-membered saturated heterocycle; R² is halogen, R²¹,OR²¹, SR²¹, COOR²¹, SO₂N(R²²)₂, N(R²²)₂, CON(R²²)₂, NR²²C(O)R²² orNR²²C(O)NR²² wherein R²¹ and each R²² is independently H, (C₁₋₆)alkyl,haloalkyl, (C₂₋₆)alkenyl, (C₃₋₇)cycloalkyl, (C₂₋₆)alkynyl,(C₅₋₇)cycloalkenyl, 6 or 10-membered aryl or Het, said R²¹ and R²² beingoptionally substituted with R²⁰, or both R²² are bonded together to forma 5, 6 or 7-membered saturated heterocycle with the nitrogen to whichthey are attached; wherein R¹⁰ and R²⁰ is each: 1 to 4 substituentswhich are, independently, halogen, OPO₃H, NO₂, cyano, azido, C(═NH)NH₂,C(═NH)NH(C₁₋₆)alkyl or C(═NH)NHCO(C₁₋₆)alkyl; or 1 to 4 substituentswhich are, independently, a) (C₁₋₆) alkyl or haloalkyl,(C₃₋₇)cycloalkyl, C₃₋₇ spirocycloalkyl optionally containing 1 or 2heteroatom, (C₂₋₆)alkenyl, (C₃₋₆)cycloalkenyl, (C₂₋₈)alkynyl, (C₁₋₆)alkyl-(C₃₋₇)cycloalkyl, all of which optionally substituted with R¹⁵⁰;b) OR¹⁰⁴ wherein R¹⁰⁴ is H, (C₁₋₆alkyl), (C₃₋₇)cycloalkyl, or(C₁₋₆)alkyl-(C₃₋₇)cycloalkyl, aryl, Het, (C₁₋₆alkyl)aryl or(C₁₋₆alkyl)Het, said alkyl, cycloalkyl, aryl, Het, (C₁₋₆alkyl)aryl or(C₁₋₆alkyl)Het being optionally substituted with R¹⁵⁰; c) OCOR¹⁰⁵wherein R¹⁰⁵ is (C₁₋₆)alkyl, (C₃₋₇)cycloalkyl,(C₁₋₆)alkyl-(C₃₋₇)cycloalkyl, Het, (C₁₋₆alkyl)aryl or (C₁₋₆alkyl)Het,said alkyl, cycloalkyl, aryl, Het, (C₁₋₆alkyl)aryl or (C₁₋₆alkyl)Hetbeing optionally substituted with R¹⁵⁰; d) SR¹⁰⁸, SO₂N(R¹⁰⁸)₂ orSO₂N(R¹⁰⁸)C(O)R¹⁰⁸ wherein each R¹⁰⁸ is independently H, (C₁₋₆)alkyl,(C₃₋₇)cycloalkyl or (C₁₋₆)alkyl-(C₃₋₇)cycloalkyl, aryl, Het,(C₁₋₆alkyl)aryl or (C₁₋₆alkyl)Het or both R¹⁰⁸ are covalently bondedtogether and to the nitrogen to which they are attached to form a 5, 6or 7-membered saturated heterocycle, said alkyl, cycloalkyl, aryl, Het,(C₁₋₆alkyl)aryl or (C₁₋₆alkyl)Het or heterocycle being optionallysubstituted with R¹⁵⁰; e) NR¹¹¹R¹¹² wherein R¹¹¹ is H, (C₁₋₆)alkyl,(C₃₋₇)cycloalkyl or (C₁₋₆)alkyl-(C₃₋₇)cycloalkyl, aryl, Het,(C₁₋₆alkyl)aryl or (C₁₋₆alkyl)Het, and R¹¹² is H, CN, (C₁₋₆)alkyl,(C₃₋₇)cycloalkyl or (C₁₋₆)alkyl-(C₃₋₇)cycloalkyl, aryl, Het,(C₁₋₆alkyl)aryl, (C₁₋₆alkyl)Het, COOR¹¹⁵ or SO₂R¹¹⁵ wherein R¹¹⁵ is(C₁₋₆)alkyl, (C₃₋₇)cycloalkyl, or (C₁₋₆)alkyl-(C₃₋₇)cycloalkyl, aryl,Het, (C₁₋₆alkyl)aryl or (C₁₋₆alkyl)Het, or both R¹¹¹ and R¹¹² arecovalently bonded together and to the nitrogen to which they areattached to form a 5, 6 or 7-membered saturated heterocycle, said alkyl,cycloalkyl, aryl, Het, (C₁₋₆alkyl)aryl or (C₁₋₆alkyl)Het, or heterocyclebeing optionally substituted with R¹⁵⁰; f) NR¹¹⁶COR¹¹⁷ wherein R¹¹⁶ andR¹¹⁷ is each H, (C₁₋₆)alkyl, (C₃₋₇)cycloalkyl,(C₁₋₆)alkyl-(C₃₋₇)cycloalkyl, aryl, Het, (C₁₋₆alkyl)aryl or(C₁₋₆alkyl)Het, said (C₁₋₆)alkyl, (C₃₋₇)cycloalkyl,(C₁₋₆)alkyl-(C₃₋₇)cycloalkyl, aryl, Het, (C₁₋₆alkyl)aryl or(C₁₋₆alkyl)Het being optionally substituted with R¹⁵⁰; g)NR¹¹⁸CONR¹¹⁹R¹²⁰, wherein R¹¹⁸, R¹¹⁹ and R¹²⁰ is each H, (C₁₋₆)alkyl,(C₃₋₇)cycloalkyl, (C₁₋₆)alkyl-(C₃₋₇)cycloalkyl, aryl, Het,(C₁₋₆alkyl)aryl or (C₁₋₆alkyl)Het, or R¹¹⁸ is covalently bonded to R¹¹⁹and to the nitrogen to which they are attached to form a 5, 6 or7-membered saturated heterocycle; or R¹¹⁹ and R¹²⁰ are covalently bondedtogether and to the nitrogen to which they are attached to form a 5, 6or 7-membered saturated heterocycle; said alkyl, cycloalkyl,(C₁₋₆)alkyl-(C₃₋₇)cycloalkyl, aryl, Het, (C₁₋₆alkyl)aryl or(C₁₋₆alkyl)Het or heterocycle being optionally substituted with R¹⁵⁰; h)NR¹²¹COCOR¹²² wherein R¹²¹ and R¹²² is each H, (C₁₋₆)alkyl,(C₃₋₇)cycloalkyl, (C₁₋₆)alkyl-(C₃₋₇)cycloalkyl, a 6- or 10-memberedaryl, Het, (C₁₋₆alkyl)aryl or (C₁₋₆alkyl)Het, said alkyl, cycloalkyl,alkyl-cycloalkyl, aryl, Het, (C₁₋₆alkyl)aryl or (C₁₋₆alkyl)Het beingoptionally substituted with R¹⁵⁰; or R¹²² is OR¹²³ or N(R¹²⁴)₂ whereinR¹²³ and each R¹²⁴ is independently H, (C₁₋₆alkyl), (C₃₋₇)cycloalkyl, or(C₁₋₆)alkyl-(C₃₋₇)cycloalkyl, aryl, Het, (C₁₋₆alkyl)aryl or(C₁₋₆alkyl)Het, or R¹²⁴ is OH or O(C₁₋₆alkyl) or both R¹²⁴ arecovalently bonded together to form a 5, 6 or 7-membered saturatedheterocycle, said alkyl, cycloalkyl, alkyl-cycloalkyl, aryl, Het,(C₁₋₆alkyl)aryl or (C₁₋₆alkyl)Het and heterocycle being optionallysubstituted with R¹⁵⁰; i) COR¹²⁷ wherein R¹²⁷ is H, (C₁₋₆)alkyl,(C₃₋₇)cycloalkyl or (C₁₋₆)alkyl-(C₃₋₇)cycloalkyl, aryl, Het,(C₁₋₆alkyl)aryl or (C₁₋₆alkyl)Het, said alkyl, cycloalkyl, aryl, Het,(C₁₋₆alkyl)aryl or (C₁₋₆alkyl)Het being optionally substituted withR¹⁵⁰; j) COOR¹²⁸ wherein R¹²⁸ is H, (C₁₋₆)alkyl, (C₃₋₇)cycloalkyl, or(C₁₋₆)alkyl-(C₃₋₇)cycloalkyl, aryl, Het, (C₁₋₆alkyl)aryl or(C₁₋₆alkyl)Het, said (C₁₋₆)alkyl, (C₃₋₇)cycloalkyl, or(C₁₋₆)alkyl-(C₃₋₇)cycloalkyl, aryl, Het, (C₁₋₆alkyl)aryl and(C₁₋₆alkyl)Het being optionally substituted with R¹⁵⁰; k) CONR¹²⁹R¹³⁰wherein R¹²⁹ and R¹³⁰ are independently H, (C₁₋₆)alkyl,(C₃₋₇)cycloalkyl, (C₁₋₆)alkyl-(C₃₋₇)cycloalkyl, aryl, Het,(C₁₋₆alkyl)aryl or (C₁₋₆alkyl)Het, or both R¹²⁹ and R¹³⁰ are covalentlybonded together and to the nitrogen to which they are attached to form a5, 6 or 7-membered saturated heterocycle, said alkyl, cycloalkyl,alkyl-cycloalkyl, aryl, Het, (C₁₋₆alkyl)aryl, (C₁₋₆alkyl)Het andheterocycle being optionally substituted with R¹⁵⁰; l) aryl, Het,(C₁₋₆alkyl)aryl or (C₁₋₆alkyl)Het, all of which being optionallysubstituted with R¹⁵⁰; and wherein R¹⁵⁰ is defined as: 1 to 3substituents which are, independently, halogen, OPO₃H, NO₂, cyano,azido, C(═NH)NH₂, C(═NH)NH(C₁₋₆)alkyl or C(═NH)NHCO(C₁₋₆)alkyl; or 1 to3 substituents which are, independently, a) (C₁₋₆) alkyl or haloalkyl,(C₃₋₇)cycloalkyl, C₃₋₇ spirocycloalkyl optionally containing 1 or 2heteroatom, (C₂₋₆)alkenyl, (C₂₋₈)alkynyl, (C₁₋₆) alkyl-(C₃₋₇)cycloalkyl,all of which optionally substituted with R¹⁶⁰; b) OR¹⁰⁴ wherein R¹⁰⁴ isH, (C₁₋₆alkyl), (C₃₋₇)cycloalkyl, or (C₁₋₆)alkyl-(C₃₋₇)cycloalkyl, aryl,Het, (C₁₋₆alkyl)aryl or (C₁₋₆alkyl)Het, said alkyl, cycloalkyl, aryl,Het, (C₁₋₆alkyl)aryl or (C₁₋₆alkyl)Het being optionally substituted withR¹⁶⁰; c) OCOR¹⁰⁵ wherein R¹⁰⁵ is (C₁₋₆)alkyl, (C₃₋₇)cycloalkyl,(C₁₋₆)alkyl-(C₃₋₇)cycloalkyl, Het, (C₁₋₆alkyl)aryl or (C₁₋₆alkyl)Het,said alkyl, cycloalkyl, aryl, Het, (C₁₋₆alkyl)aryl or (C₁₋₆alkyl)Hetbeing optionally substituted with R¹⁶⁰; d) SR¹⁰⁸, SO₂N(R¹⁰⁸)₂ orSO₂N(R¹⁰⁸)C(O)R¹⁰⁸ wherein each R¹⁰⁸ is independently H, (C₁₋₆)alkyl,(C₃₋₇)cycloalkyl or (C₁₋₆)alkyl-(C₃₋₇)cycloalkyl, aryl, Het,(C₁₋₆alkyl)aryl or (C₁₋₆alkyl)Het or both R¹⁰⁸ are covalently bondedtogether and to the nitrogen to which they are attached to form a 5, 6or 7-membered saturated heterocycle, said alkyl, cycloalkyl, aryl, Het,(C₁₋₆alkyl)aryl or (C₁₋₆alkyl)Het or heterocycle being optionallysubstituted with R¹⁶⁰; e) NR¹¹¹R¹¹² wherein R¹¹¹ is H, (C₁₋₆)alkyl,(C₃₋₇)cycloalkyl or (C₁₋₆)alkyl-(C₃₋₇)cycloalkyl, aryl, Het,(C₁₋₆alkyl)aryl or (C₁₋₆alkyl)Het, and R¹¹² is H, CN, (C₁₋₆)alkyl,(C₃₋₇)cycloalkyl or (C₁₋₆)alkyl-(C₃₋₇)cycloalkyl, aryl, Het,(C₁₋₆alkyl)aryl, (C₁₋₆alkyl)Het, COOR¹¹⁵ or SO₂R¹¹⁵ wherein R¹¹⁵ is(C₁₋₆)alkyl, (C₃₋₇)cycloalkyl, or (C₁₋₆)alkyl-(C₃₋₇)cycloalkyl, aryl,Het, (C₁₋₆alkyl)aryl or (C₁₋₆alkyl)Het, or both R¹¹¹ and R¹¹² arecovalently bonded together and to the nitrogen to which they areattached to form a 5, 6 or 7-membered saturated heterocycle, said alkyl,cycloalkyl, aryl, Het, (C₁₋₆alkyl)aryl or (C₁₋₆alkyl)Het, or heterocyclebeing optionally substituted with R¹⁶⁰; f) NR¹¹⁶COR¹¹⁷ wherein R¹¹⁶ andR¹¹⁷ is each H, (C₁₋₆)alkyl, (C₃₋₇)cycloalkyl,(C₁₋₆)alkyl-(C₃₋₇)cycloalkyl, aryl, Het, (C₁₋₆alkyl)aryl or(C₁₋₆alkyl)Het, said (C₁₋₆)alkyl, (C₃₋₇)cycloalkyl,(C₁₋₆)alkyl-(C₃₋₇)cycloalkyl, aryl, Het, (C₁₋₆alkyl)aryl or(C₁₋₆alkyl)Het being optionally substituted with R¹⁶⁰; g)NR¹¹⁸CONR¹¹⁹R¹²⁰, wherein R¹¹⁸, R¹¹⁹ and R¹²⁰ is each H, (C₁₋₆)alkyl,(C₃₋₇)cycloalkyl, (C₁₋₆)alkyl-(C₃₋₇)cycloalkyl, aryl, Het,(C₁₋₆alkyl)aryl or (C₁₋₆alkyl)Het, or R¹¹⁸ is covalently bonded to R¹¹⁹and to the nitrogen to which they are attached to form a 5, 6 or7-membered saturated heterocycle; or R¹¹⁹ and R¹²⁰ are covalently bondedtogether and to the nitrogen to which they are attached to form a 5, 6or 7-membered saturated heterocycle; said alkyl, cycloalkyl,(C₁₋₆)alkyl-(C₃₋₇)cycloalkyl, aryl, Het, (C₁₋₆alkyl)aryl or(C₁₋₆alkyl)Het or heterocycle being optionally substituted with R¹⁶⁰; h)NR¹²¹COCOR¹²² wherein R¹²¹ and R¹²² is each H, (C₁₋₆)alkyl,(C₃₋₇)cycloalkyl, (C₁₋₆)alkyl-(C₃₋₇)cycloalkyl, a 6- or 10-memberedaryl, Het, (C₁₋₆alkyl)aryl or (C₁₋₆alkyl)Het, said alkyl, cycloalkyl,alkyl-cycloalkyl, aryl, Het, (C₁₋₆alkyl)aryl or (C₁₋₆alkyl)Het beingoptionally substituted with R¹⁶⁰; or R¹²² is OR¹²³ or N(R¹²⁴)₂ whereinR¹²³ and each R¹²⁴ is independently H, (C₁₋₆alkyl), (C₃₋₇)cycloalkyl, or(C₁₋₆)alkyl-(C₃₋₇)cycloalkyl, aryl, Het, (C₁₋₆alkyl)aryl or(C₁₋₆alkyl)Het, or R¹²⁴ is OH or O(C₁₋₆alkyl) or both R¹²⁴ arecovalently bonded together to form a 5, 6 or 7-membered saturatedheterocycle, said alkyl, cycloalkyl, alkyl-cycloalkyl, aryl, Het,(C₁₋₆alkyl)aryl or (C₁₋₆alkyl)Het and heterocycle being optionallysubstituted with R¹⁶⁰; i) COR¹²⁷ wherein R¹²⁷ is H, (C₁₋₆)alkyl,(C₃₋₇)cycloalkyl or (C₁₋₆)alkyl-(C₃₋₇)cycloalkyl, aryl, Het,(C₁₋₆alkyl)aryl or (C₁₋₆alkyl)Het, said alkyl, cycloalkyl, aryl, Het,(C₁₋₆alkyl)aryl or (C₁₋₆alkyl)Het being optionally substituted withR¹⁶⁰; j) tetrazole, COOR¹²⁸ wherein R¹²⁸ is H, (C₁₋₆)alkyl,(C₃₋₇)cycloalkyl, or (C₁₋₆)alkyl-(C₃₋₇)cycloalkyl, aryl, Het,(C₁₋₆alkyl)aryl or (C₁₋₆alkyl)Het, said (C₁₋₆)alkyl, (C₃₋₇)cycloalkyl,or (C₁₋₆)alkyl-(C₃₋₇)cycloalkyl, aryl, Het, (C₁₋₆alkyl)aryl and(C₁₋₆alkyl)Het being optionally substituted with R¹⁶⁰; and k)CONR¹²⁹R¹³⁰ wherein R¹²⁹ and R¹³⁰ are independently H, (C₁₋₆)alkyl,(C₃₋₇)cycloalkyl, (C₁₋₆)alkyl-(C₃₋₇)cycloalkyl, aryl, Het,(C₁₋₆alkyl)aryl or (C₁₋₆alkyl)Het, or both R¹²⁹ and R¹³⁰ are covalentlybonded together and to the nitrogen to which they are attached to form a5, 6 or 7-membered saturated heterocycle, said alkyl, cycloalkyl,alkyl-cycloalkyl, aryl, Het, (C₁₋₆alkyl)aryl, (C₁₋₆alkyl)Het andheterocycle being optionally substituted with R¹⁶⁰; wherein R¹⁶⁰ isdefined as 1 or 2 substituents which are, independently, tetrazole,halogen, CN, C₁₋₆alkyl, haloalkyl, COOR¹⁶¹, SO₃H, SR¹⁶¹, SO₂R¹⁶¹, OR¹⁶¹,N(R¹⁶²)₂, SO₂N(R¹⁶²)₂, NR¹⁶²COR¹⁶² or CON(R¹⁶²)₂, wherein R¹⁶¹ and eachR¹⁶² is independently H, (C₁₋₆)alkyl, (C₃₋₇)cycloalkyl or(C₁₋₆)alkyl-(C₃₋₇)cycloalkyl; or both R¹⁶² are covalently bondedtogether and to the nitrogen to which they are attached to form a 5, 6or 7-membered saturated heterocycle, R³ is, independently,(C₃₋₇)cycloalkyl, (C₅₋₇)cycloalkenyl, (C₆₋₁₀)bicycloalkyl or(C₆₋₁₀)bicycloalkenyl, said cycloalkyl and bicycloalkyl being optionallysubstituted with from 1 to 4 substituents which are, independently,halogen, or a) (C₁₋₆)alkyl optionally substituted with: OR³¹ or SR³¹wherein R³¹ is H, (C₁₋₆alkyl), (C₃₋₇)cycloalkyl,(C₁₋₆)alkyl-(C₃₋₇)cycloalkyl, aryl, Het, (C₁₋₆)alkyl-aryl or(C₁₋₆)alkyl-Het; or N(R³²)₂ wherein each R³² is independently H,(C₁₋₆)alkyl, (C₃₋₇)cycloalkyl, (C₁₋₆)alkyl-(C₃₋₇)cycloalkyl, aryl, Het,(C₁₋₆)alkyl-aryl or (C₁₋₆)alkyl-Het; or both R³² are covalently bondedtogether and to the nitrogen to which they are attached to form a 5, 6or 7-membered saturated heterocycle; b) OR³³ wherein R³³ is H,(C₁₋₆)alkyl, (C₃₋₇)cycloalkyl or (C₁₋₆)alkyl-(C₃₋₇)cycloalkyl, aryl,Het, (C₁₋₆)alkyl-aryl or (C₁₋₆)alkyl-Het; c) SR³⁴ wherein R³⁴ is H,(C₁₋₆)alkyl, (C₃₋₇)cycloalkyl, or (C₁₋₆)alkyl-(C₃₋₇)cycloalkyl, aryl,Het, (C₁₋₆)alkyl-aryl or (C₁₋₆)alkyl-Het; and d) N(R³⁵)₂ wherein eachR³⁵ is independently H, (C₁₋₆)alkyl, (C₃₋₇)cycloalkyl,(C₁₋₆)alkyl-(C₃₋₇)cycloalkyl, aryl, Het, (C₁₋₆)alkyl-aryl or(C₁₋₆)alkyl-Het; or both R³⁵ are covalently bonded together and to thenitrogen to which they are attached to form a 5, 6 or 7-memberedsaturated heterocycle; K is N or CR⁴, wherein R⁴ is H, halogen,(C₁₋₆)alkyl, haloalkyl, (C₃₋₇)cycloalkyl or(C₁₋₆)alkyl-(C₃₋₇)cycloalkyl; or R⁴ is OR⁴¹ or SR⁴¹, COR⁴¹ or NR⁴¹COR⁴¹wherein each R⁴¹ is independently H, (C₁₋₆)alkyl), (C₃₋₇)cycloalkyl or(C₁₋₆)alkyl-(C₃₋₇)cycloalkyl; or R⁴ is NR⁴²R⁴³ wherein R⁴² and R⁴³ areeach independently H, (C₁₋₆)alkyl, (C₃₋₇)cycloalkyl,(C₁₋₆)alkyl-(C₃₋₇)cycloalkyl, or both R⁴² and R⁴³ are covalently bondedtogether and to the nitrogen to which they are attached to form a 5, 6or 7-membered saturated heterocycle; L is N or CR⁵, wherein R⁵ has thesame definition as R⁴ defined above; M is N or CR⁷, wherein R⁷ has thesame definition as R⁴ defined above; with the proviso that one and onlyone of K, L and M is N; Z is OR⁶, wherein R⁶ is H, (C₁₋₆)alkyl beingoptionally substituted with: halo, hydroxy, carboxy, amino, C₁₋₆ alkoxy,C₁₋₆alkoxycarbonyl, and C₁₋₆ alkylamino; or R⁶ is C₁₋₆ alkylaryloptionally substituted with: halogen, cyano, nitro, C₁₋₆ alkyl,C₁₋₆haloalkyl, C₁₋₆alkanoyl, —(CH₂)₁₋₆—COOR⁷, —(CH₂)₁₋₆—CONR⁷R⁸,—(CH₂)₁₋₆—NR⁷R⁸, —(CH₂)₁₋₆—NR⁷COR⁸, —(CH₂)₁₋₆—NHSO₂R⁷, —(CH₂)₁₋₆—OR⁷,—(CH₂)₁₋₆—SR⁷, —(CH₂)₁₋₆—SO₂R⁷, and —(CH₂)₁₋₆—SO₂NR⁷R⁸, wherein each R⁷and each R⁸ is H or C₁₋₆ alkyl, or Z is NR⁹R¹⁰ wherein each of R⁹ andR¹⁰ is, independently, H, C₁₋₆alkoxy, or C₁₋₆alkyl optionallysubstituted with halo, hydroxy, carboxy, amino, C₁₋₆ alkoxy,C₁₋₆alkoxycarbonyl, and C₁₋₆ alkylamino; or an enantiomer,diastereoisomer, tautomer or pharmaceutically acceptable salt thereof.2. The compound according to claim 1, wherein M, K and L are eachindependently CH or N, provided that only one of M, K and L is N.
 3. Thecompound according to claim 1, having the following formula:

wherein R¹, R², R³ and Z are as defined in claim
 1. 4. The compoundaccording to claim 1, wherein R¹ is H or (C₁₋₆)alkyl.
 5. The compoundaccording to claim 4, wherein R¹ is H, CH₃, isopropyl, or isobutyl. 6.The compound according to claim 5, wherein R¹ is H or CH₃.
 7. Thecompound according to claim 6, wherein R¹ is CH₃.
 8. The compoundaccording to claim 1, wherein R² is, independently, H, halogen,(C₂₋₆)alkenyl, (C₅₋₇)cycloalkenyl, 6 or 10-membered aryl or Het; wherein(C₂₋₆)alkenyl, (C₅₋₇)cycloalkenyl, aryl or Het is optionally substitutedwith R²⁰, wherein R²⁰ is defined as: 1 to 4 substituents which are,independently of one another, halogen, NO₂, cyano, azido, C(═NH)NH₂,C(═NH)NH(C₁₋₆)alkyl or C(═NH)NHCO(C₁₋₆)alkyl; or 1 to 4 substituentswhich are, independently of one another, a) (C₁₋₆) alkyl or haloalkyl,(C₃₋₇)cycloalkyl, (C₂₋₆)alkenyl, (C₂₋₈)alkynyl, (C₁₋₆)alkyl-(C₃₋₇)cycloalkyl, all of which optionally substituted with R¹⁵⁰;b) OR¹⁰⁴ wherein R¹⁰⁴ is H, (C₁₋₆alkyl), (C₃₋₇)cycloalkyl, or(C₁₋₆)alkyl-(C₃₋₇)cycloalkyl, aryl, Het, (C₁₋₆alkyl)aryl or(C₁₋₆alkyl)Het, said alkyl, cycloalkyl, aryl, Het, (C₁₋₆alkyl)aryl or(C₁₋₆alkyl)Het being optionally substituted with R¹⁵⁰; c) OCOR¹⁰⁵wherein R¹⁰⁵ is (C₁₋₆)alkyl, (C₃₋₇)cycloalkyl,(C₁₋₆)alkyl-(C₃₋₇)cycloalkyl, Het, (C₁₋₆alkyl)aryl or (C₁₋₆alkyl)Het,said alkyl, cycloalkyl, aryl, Het, (C₁₋₆alkyl)aryl or (C₁₋₆alkyl)Hetbeing optionally substituted with R¹⁵⁰; d) SR¹⁰⁸, SO₂N(R¹⁰⁸)₂ orSO₂N(R¹⁰⁸)C(O)R¹⁰⁸ wherein each R¹⁰⁸ is independently H, (C₁₋₆)alkyl,(C₃₋₇)cycloalkyl or (C₁₋₆)alkyl-(C₃₋₇)cycloalkyl, aryl, Het,(C₁₋₆alkyl)aryl or (C₁₋₆alkyl)Het or both R¹⁰⁸ are covalently bondedtogether and to the nitrogen to which they are attached to form a 5, 6or 7-membered saturated heterocycle, said alkyl, cycloalkyl, aryl, Het,(C₁₋₆alkyl)aryl or (C₁₋₆alkyl)Het or heterocycle being optionallysubstituted with R¹⁵⁰; e) NR¹¹¹R¹¹² wherein R¹¹¹ is H, (C₁₋₆)alkyl,(C₃₋₇)cycloalkyl or (C₁₋₆)alkyl-(C₃₋₇)cycloalkyl, aryl, Het,(C₁₋₆alkyl)aryl or (C₁₋₆alkyl)Het, and R¹¹² is H, CN, (C₁₋₆)alkyl,(C₃₋₇)cycloalkyl or (C₁₋₆)alkyl-(C₃₋₇)cycloalkyl, aryl, Het,(C₁₋₆alkyl)aryl, (C₁₋₆alkyl)Het, COOR¹¹⁵ or SO₂R¹¹⁵ wherein R¹¹⁵ is(C₁₋₆)alkyl, (C₃₋₇)cycloalkyl, or (C₁₋₆)alkyl-(C₃₋₇)cycloalkyl, aryl,Het, (C₁₋₆alkyl)aryl or (C₁₋₆alkyl)Het, or both R¹¹¹ and R¹¹² arecovalently bonded together and to the nitrogen to which they areattached to form a 5, 6 or 7-membered saturated heterocycle, said alkyl,cycloalkyl, aryl, Het, (C₁₋₆alkyl)aryl or (C₁₋₆alkyl)Het, or heterocyclebeing optionally substituted with R¹⁵⁰; f) NR¹¹⁶COR¹¹⁷ wherein R¹¹⁶ andR¹¹⁷ is each H, (C₁₋₆)alkyl, (C₃₋₇)cycloalkyl,(C₁₋₆)alkyl-(C₃₋₇)cycloalkyl, aryl, Het, (C₁₋₆alkyl)aryl or(C₁₋₆alkyl)Het, said (C₁₋₆)alkyl, (C₃₋₇)cycloalkyl,(C₁₋₆)alkyl-(C₃₋₇)cycloalkyl, aryl, Het, (C₁₋₆alkyl)aryl or(C₁₋₆alkyl)Het being optionally substituted with R¹⁵⁰; g)NR¹¹⁸CONR¹¹⁹R¹²⁰, wherein R¹¹⁸, R¹¹⁹ and R¹²⁰ is each H, (C₁₋₆)alkyl,(C₃₋₇)cycloalkyl, (C₁₋₆)alkyl-(C₃₋₇)cycloalkyl, aryl, Het,(C₁₋₆alkyl)aryl or (C₁₋₆alkyl)Het, or R¹¹⁸ is covalently bonded to R¹¹⁹and to the nitrogen to which they are attached to form a 5, 6 or7-membered saturated heterocycle; or R¹¹⁹ and R¹²⁰ are covalently bondedtogether and to the nitrogen to which they are attached to form a 5, 6or 7-membered saturated heterocycle; said alkyl, cycloalkyl,(C₁₋₆)alkyl-(C₃₋₇)cycloalkyl, aryl, Het, (C₁₋₆alkyl)aryl or(C₁₋₆alkyl)Het or heterocycle being optionally substituted with R¹⁵⁰; h)NR¹²¹COCOR¹²² wherein R¹²¹ and R¹²² is each H, (C₁₋₆)alkyl,(C₃₋₇)cycloalkyl, (C₁₋₆)alkyl-(C₃₋₇)cycloalkyl, a 6- or 10-memberedaryl, Het, (C₁₋₆alkyl)aryl or (C₁₋₆alkyl)Het, said alkyl, cycloalkyl,alkyl-cycloalkyl, aryl, Het, (C₁₋₆alkyl)aryl or (C₁₋₆alkyl)Het beingoptionally substituted with R¹⁵⁰; or R¹²² is OR¹²³ or N(R¹²⁴)₂ whereinR¹²³ and each R¹²⁴ is independently H, (C₁₋₆alkyl), (C₃₋₇)cycloalkyl, or(C₁₋₆)alkyl-(C₃₋₇)cycloalkyl, aryl, Het, (C₁₋₆alkyl)aryl or(C₁₋₆alkyl)Het, or R¹²⁴ is OH or O(C₁₋₆alkyl) or both R¹²⁴ arecovalently bonded together to form a 5, 6 or 7-membered saturatedheterocycle, said alkyl, cycloalkyl, alkyl-cycloalkyl, aryl, Het,(C₁₋₆alkyl)aryl or (C₁₋₆alkyl)Het and heterocycle being optionallysubstituted with R¹⁵⁰; i) COR¹²⁷ wherein R¹²⁷ is H, (C₁₋₆)alkyl,(C₃₋₇)cycloalkyl or (C₁₋₆)alkyl-(C₃₋₇)cycloalkyl, aryl, Het,(C₁₋₆alkyl)aryl or (C₁₋₆alkyl)Het, said alkyl, cycloalkyl, aryl, Het,(C₁₋₆alkyl)aryl or (C₁₋₆alkyl)Het being optionally substituted withR¹⁵⁰; j) COOR¹²⁸ wherein R¹²⁸ is H, (C₁₋₆)alkyl, (C₃₋₇)cycloalkyl, or(C₁₋₆)alkyl-(C₃₋₇)cycloalkyl, aryl, Het, (C₁₋₆alkyl)aryl or(C₁₋₆alkyl)Het, said (C₁₋₆)alkyl, (C₃₋₇)cycloalkyl, or(C₁₋₆)alkyl-(C₃₋₇)cycloalkyl, aryl, Het, (C₁₋₆alkyl)aryl and(C₁₋₆alkyl)Het being optionally substituted with R¹⁵⁰; k) CONR¹²⁹R¹³⁰wherein R¹²⁹ and R¹³⁰ are independently H, (C₁₋₆)alkyl,(C₃₋₇)cycloalkyl, (C₁₋₆)alkyl-(C₃₋₇)cycloalkyl, aryl, Het,(C₁₋₆alkyl)aryl or (C₁₋₆alkyl)Het, or both R¹²⁹ and R¹³⁰ are covalentlybonded together and to the nitrogen to which they are attached to form a5, 6 or 7-membered saturated heterocycle, said alkyl, cycloalkyl,alkyl-cycloalkyl, aryl, Het, (C₁₋₆alkyl)aryl, (C₁₋₆alkyl)Het andheterocycle being optionally substituted with R¹⁵⁰; l) aryl, Het,(C₁₋₆alkyl)aryl or (C₁₋₆alkyl)Het, all of which being optionallysubstituted with R¹⁵⁰; wherein R¹⁵⁰ is: 1 to 3 substituents which are,independently of one another, halogen, NO₂, cyano or azido; or 1 to 3substituents which are, independently of one another, a) (C₁₋₆) alkyl orhaloalkyl, (C₃₋₇)cycloalkyl, (C₂₋₆)alkenyl, (C₂₋₈)alkynyl, (C₁₋₆)alkyl-(C₃₋₇)cycloalkyl, all of which optionally substituted with R¹⁶⁰;b) OR¹⁰⁴ wherein R¹⁰⁴ is H, (C₁₋₆alkyl) or (C₃₋₇)cycloalkyl, said alkylor cycloalkyl optionally substituted with R¹⁶⁰; d) SR¹⁰⁸, SO₂N(R¹⁰⁸)₂ orSO₂N(R¹⁰⁸)C(O)R¹⁰⁸ wherein each R¹⁰⁸ is independently H, (C₁₋₆)alkyl,(C₃₋₇)cycloalkyl or (C₁₋₆)alkyl-(C₃₋₇)cycloalkyl, aryl, Het, or bothR¹⁰⁸ are covalently bonded together and to the nitrogen to which theyare attached to form a 5, 6 or 7-membered saturated heterocycle, saidalkyl, cycloalkyl, aryl, Het and heterocycle being optionallysubstituted with R¹⁶⁰; e) NR¹¹¹R¹¹² wherein R¹¹¹ is H, (C₁₋₆)alkyl, or(C₃₋₇)cycloalkyl, and R¹¹² is H, (C₁₋₆)alkyl or (C₃₋₇)cycloalkyl,COOR¹¹⁵ or SO₂R¹¹⁵ wherein R¹¹⁵ is (C₁₋₆)alkyl or (C₃₋₇)cycloalkyl, orboth R¹¹¹ and R¹¹² are covalently bonded together and to the nitrogen towhich they are attached to form a 5, 6 or 7-membered saturatedheterocycle, said alkyl, cycloalkyl and heterocycle being optionallysubstituted with R¹⁶⁰; f) NR¹¹⁶COR¹¹⁷ wherein R¹¹⁶ and R¹¹⁷ is each H,(C₁₋₆)alkyl or (C₃₋₇)cycloalkyl said (C₁₋₆)alkyl and (C₃₋₇)cycloalkylbeing optionally substituted with R¹⁶⁰; g) NR¹¹⁸CONR¹¹⁹R¹²⁰, whereinR¹¹⁸, R¹¹⁹ and R¹²⁰ is each H, (C₁₋₆)alkyl or (C₃₋₇)cycloalkyl, or R¹¹⁸is covalently bonded to R¹¹⁹ and to the nitrogen to which they areattached to form a 5, 6 or 7-membered saturated heterocycle; or R¹¹⁹ andR¹²⁰ are covalently bonded together and to the nitrogen to which theyare attached to form a 5, 6 or 7-membered saturated heterocycle; saidalkyl, cycloalkyl, and heterocycle being optionally substituted withR¹⁶⁰; h) NR¹²¹COCOR¹²² wherein R¹²¹ is H, (C₁₋₆)alkyl or(C₃₋₇)cycloalkyl, said alkyl and cycloalkyl being optionally substitutedwith R¹⁶⁰; or R¹²² is OR¹²³ or N(R¹²⁴)₂ wherein R¹²³ and each R¹²⁴ isindependently H, (C₁₋₆alkyl) or (C₃₋₇)cycloalkyl, or both R¹²⁴ arecovalently bonded together to form a 5, 6 or 7-membered saturatedheterocycle, said alkyl, cycloalkyl and heterocycle being optionallysubstituted with R¹⁶⁰; i) COR¹²⁷ wherein R¹²⁷ is H, (C₁₋₆)alkyl or(C₃₋₇)cycloalkyl, said alkyl and cycloalkyl being optionally substitutedwith R¹⁶⁰; j) COOR¹²⁸ wherein R¹²⁸ is H, (C₁₋₆)alkyl or(C₃₋₇)cycloalkyl, said (C₁₋₆)alkyl and (C₃₋₇)cycloalkyl being optionallysubstituted with R¹⁶⁰; and k) CONR¹²⁹R¹³⁰ wherein R¹²⁹ and R¹³⁰ areindependently H, (C₁₋₆)alkyl or (C₃₋₇)cycloalkyl, or both R¹²⁹ and R¹³⁰are covalently bonded together and to the nitrogen to which they areattached to form a 5, 6 or 7-membered saturated heterocycle, said alkyl,cycloalkyl and heterocycle being optionally substituted with R¹⁶⁰;wherein R¹⁶⁰ is defined as 1 or 2 substituents which are, independentlyof one another, halogen, CN, C₁₋₆alkyl, haloalkyl, COOR¹⁶¹, OR¹⁶¹,N(R¹⁶²)₂, SO₂N(R¹⁶²)₂, NR¹⁶²COR¹⁶² or CON(R¹⁶²)₂, wherein R¹⁶¹ and eachR¹⁶² is independently H, (C₁₋₆)alkyl, (C₃₋₇)cycloalkyl or(C₁₋₆)alkyl-(C₃₋₇)cycloalkyl; or both R¹⁶² are covalently bondedtogether and to the nitrogen to which they are attached to form a 5, 6or 7-membered saturated heterocycle.
 9. The compound according to claim8, wherein R² is, independently, aryl or Het, each optionallymonosubstituted or disubstituted with a substituent which is halogen,haloalkyl, N₃, or a) (C₁₋₆)alkyl optionally substituted with OH, orO(C₁₋₆)alkyl; b) (C₁₋₆)alkoxy; e) NR¹¹¹R¹¹² wherein both R¹¹¹ and R¹¹²are independently H, (C₁₋₆)alkyl, (C₃₋₇)cycloalkyl, or R¹¹² is 6- or10-membered aryl, Het, (C₁₋₆)alkyl-aryl or (C₁₋₆)alkyl-Het; or both R¹¹¹and R¹¹² are covalently bonded together and to the nitrogen to whichthey are attached to form a 5, 6 or 7-membered saturatednitrogen-containing heterocycle, each of said alkyl, cycloalkyl, aryl,Het, alkyl-aryl or alkyl-Het; being optionally substituted with halogenor: OR¹⁶¹ or N(R¹⁶²)₂, wherein R¹⁶¹ and each R¹⁶² is independently H,(C₁₋₆)alkyl, or both R¹⁶² are covalently bonded together and to thenitrogen to which they are attached to form a 5, 6 or 7-memberedsaturated nitrogen-containing heterocycle; f) NHCOR¹¹⁷ wherein R¹¹⁷ is(C₁₋₆)alkyl, O(C₁₋₆)alkyl or O(C₃₋₇)cycloalkyl; i) CO-aryl; or k) CONH₂,CONH(C₁₋₆alkyl), CON(C₁₋₆alkyl)₂, CONH-aryl, or CONHC₁₋₆alkyl-aryl. 10.The compound according to claim 9, wherein R² is aryl or Het, eachoptionally monosubstituted or disubstituted with substituents halogen,haloalkyl, or a) (C₁₋₆)alkyl optionally substituted with OH, orO(C₁₋₆)alkyl; b) (C₁₋₆)alkoxy; and e) NR¹¹¹R¹¹² wherein both R¹¹¹ andR¹¹² are independently H, (C₁₋₆)alkyl, (C₃₋₇)cycloalkyl, or R¹¹² is 6-or 10-membered aryl, Het, (C₁₋₆)alkyl-aryl or (C₁₋₆)alkyl-Het; or bothR¹¹¹ and R¹¹² are covalently bonded together and to the nitrogen towhich they are attached to form a 5, 6 or 7-membered saturatednitrogen-containing heterocycle, each of said alkyl, cycloalkyl, aryl,Het, alkyl-aryl or alkyl-Het; or being optionally substituted withhalogen or: OR¹⁶¹ or N(R¹⁶²)₂, wherein R¹⁶¹ and each R¹⁶² isindependently H, (C₁₋₆)alkyl, or both R¹⁶² are covalently bondedtogether and to the nitrogen to which they are attached to form a 5, 6or 7-membered saturated nitrogen-containing heterocycle.
 11. Thecompound according to claim 10, wherein R² is phenyl or a heterocyclewhich is

which is optionally substituted as defined in claim
 10. 12. The compoundaccording to claim 1, wherein R² is, independently,


13. The compound according to claim 12, wherein R² is


14. The compound according to claim 13, wherein R² is


15. The compound according to claim 1, wherein R³ is selected from(C₃₋₇)cycloalkyl, (C₃₋₇)cycloalkenyl, (C₆₋₁₀)bicycloalkyl or(C₆₋₁₀)bicycloalkenyl.
 16. The compound according to claim 15, whereinR³ is (C₃₋₇)cycloalkyl.
 17. The compound according to claim 16, whereinR³ is cyclopentyl, or cyclohexyl.
 18. The compound according to claim 1,wherein Y¹ is O.
 19. The compound according to claim 1, wherein Z isOR⁶, wherein R⁶ is H or (C₁₋₆)alkyl which is optionally substitutedwith: halo, hydroxy, carboxy, amino, C₁₋₆ alkoxy, C₁₋₆alkoxycarbonyl, orC₁₋₆ alkylamino; or R⁶ is C₁₋₆ alkylaryl optionally substituted with:halogen, cyano, nitro, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₁₋₆alkanoyl,—(CH₂)₁₋₆—COOR⁷, —(CH₂)₁₋₆—CONR⁷R⁸, —(CH₂)₁₋₆—NR⁷R⁸, —(CH₂)₁₋₆—NR⁷COR⁸,—(CH₂)₁₋₆—NHSO₂R⁷, —(CH₂)₁₋₆—OR⁷, —(CH₂)₁₋₆—SR⁷, —(CH₂)₁₋₆—SO₂R⁷, or—(CH₂)₁₋₆—SO₂NR⁷R⁸, wherein each R⁷ and each R⁸ is H or C₁₋₆ alkyl, or Zis NR⁹R¹⁰ wherein each of R⁹ and R¹⁰ are, independently of one another,H, C₁₋₆alkoxy, or C₁₋₆alkyl optionally substituted with halo, hydroxy,carboxy, amino, C₁₋₆ alkoxy, C₁₋₆alkoxycarbonyl, and C₁₋₆ alkylamino.20. The compound according to claim 19, wherein Z is OH or O(C₁₋₆alkyl)or Z is NR⁹R¹⁰ wherein R⁹ is H and R¹⁰ is H or C₁₋₆alkyl.
 21. Thecompound according to claim 20, wherein Z is OH.
 22. A compound offormula:

wherein A, R², R³ and Z are as defined below: Cpd. # A R² R³ Z 201 N—Mephenyl cyclohexyl OH; and 202 N—Me

cyclohexyl OH.


23. A compound represented by Formula Ia:

wherein: A is NR¹; B is CR³; R¹ is H, (C₁₋₆)alkyl, benzyl, (C₁₋₆alkyl)-(C₆₋₁₀aryl), (C₁₋₆ alkyl)-5- or 6-membered heterocycle having 1to 4 heteroatoms which are, independently, O, N, or S, and 5- or6-membered heterocycle having 1 to 4 heteroatoms which are,independently, O, N, or S, wherein said benzyl and said heteroatom areoptionally substituted with from 1 to 4 substituents COOH, COO(C₁₋₆alkyl), halogen, or (C₁₋₆ alkyl); R² is H, halogen, (C₁₋₆)alkyl,(C₃₋₇)cycloalkyl, phenyl, 5- or 6-membered heterocycle having 1 to 4heteroatoms which are, independently, O, N, or S, pyridine-N-oxide, or9- or 10-membered heterobicycle having 1 to 4 heteroatoms which are,independently, O, N, or S, said phenyl, heterocycle and heterobicyclebeing optionally substituted with from 1 to 4 substituents, which areindependently, halogen, C(halogen)₃, (C₁₋₆)alkyl, OH, O(C₁₋₆ alkyl),NH₂, or N(C₁₋₆ alkyl)₂; R³ is norbornane or (C₃₋₇)cycloalkyl; M is N,CR⁴, or COR⁵, wherein R⁴ is H, halogen, or (C₁₋₆ alkyl); and R⁵ is H or(C₁₋₆ alkyl); K and L are N or CH; with the proviso that one and onlyone of M, K and L is N; — represents either a single or a double bond; Yis O; Z is OR⁶, wherein R⁶ is H, (C₁₋₆)alkyl, wherein said alkyl isoptionally substituted with from 1 to 4 substituents which are,independently, OH, COOH, COO(C₁₋₆)alkyl, or (C₁₋₆)alkyl, said alkylbeing optionally substituted with from 1 to 4 substituents which are,independently, COOH, NHCO(C₁₋₆ alkyl), NH₂, NH(C₁₋₆ alkyl), or N(C₁₋₆alkyl)₂; or a salt thereof.
 24. A pharmaceutical composition for thetreatment of HCV infection, comprising an effective amount of a compoundof formula I according to claim 1, or a pharmaceutically acceptable saltthereof, and a pharmaceutically acceptable carrier.
 25. Thepharmaceutical composition according to claim 24, further comprising animmunomodulatory agent.
 26. The pharmaceutical composition according toclaim 25, wherein said immunomodulatory agent is α-interferon,β-interferon, δ-interferon, -interferon, or ω-interferon.
 27. Thepharmaceutical composition according to claim 24, further comprisingribavirin or amantadine.
 28. The pharmaceutical composition according toclaim 24, further comprising another inhibitor of HCV polymerase. 29.The pharmaceutical composition according to claim 28, further comprisingan inhibitor of other HCV target, wherein said inhibitor is helicase,polymerase, metalloprotease or IRES.
 30. A method of treating HCVinfection in a mammal, comprising administering to the mammal aneffective amount of a pharmaceutical composition according to claim 24.31. A compound of the formula I according to claim 1, wherein Y¹ is Oand Z is OR⁶.